Patent Publication Number: US-2004043021-A1

Title: Nucleotide and amino acid sequences relating to respiratory diseases and obesity

Description:
RELATED APPLICATIONS  
     [0001] This application claims priority to U.S. Application Serial No. 60/328,424, filed Oct. 11, 2001, which is hereby incorporated by reference in its entirety. 
    
    
     
       FIELD OF THE INVENTION  
       [0002] This invention relates to ADAM family genes and other Interactor genes identified to be associated with asthma, atopy, obesity, inflammatory bowel disease, and other human diseases. The invention also relates to the nucleotide sequences of these genes, including genomic DNA sequences, cDNA sequences, single nucleotide polymorphisms, alleles, haplotypes, and alternate splice variants. The invention further relates to isolated nucleic acids comprising these nucleotide sequences, and isolated polypeptides or peptides encoded thereby. Also related are expression vectors and host cells comprising the disclosed nucleic acids or fragments thereof, as well as antibodies that bind to the encoded polypeptides or peptides. The present invention further relates to ligands that modulate the activity of the disclosed genes or gene products. The invention further relates to diagnostics and therapeutics for various diseases, including asthma, utilizing ADAM genes and other Interactor genes, polypeptides, peptides, antibodies, or ligands.  
       BACKGROUND  
       [0003] Asthma has been linked to specific markers on human chromosomes (Wilson et al., 1998,  Genomics,  53: 251-259). Furthermore, asthma has been associated with other diseases, particularly, inflammatory lung disease phenotypes such as Chronic Obstructive Lung Disease (COPD), Adult Respiratory Distress Syndrome (ARDS), atopy, obesity, and inflammatory bowel disease.  
       [0004] Recently, an ADAM (A Disintegrin And Metalloprotease) family gene, ADAM33 (Gene 216), has been linked to asthma as described in U.S. patent application Ser. No. 09/834,597. The ADAM gene family, of which there are currently 33 members, is a sub-group of the zinc-dependent metalloprotease superfamily. ADAMs have a complex domain organization that includes a signal sequence, propeptide, metalloprotease, disintegrin, cysteine-rich, and epidermal growth factor-like domains, as well as a transmembrane region and cytoplasmic tail. ADAM proteins have been implicated in many processes such as proteolysis in the secretory pathway and extracellular matrix, extra- and intra-cellular signaling, processing of plasma membrane proteins and procytokine conversion.  
       [0005] Thus, there is a need in the art for the identification of other ADAM gene family members, substrates, and interactors that are involved in asthma and related disorders. Identification and characterization of such genes will allow the development of effective diagnostics and therapeutic means to diagnose, prevent, and treat lung related disorders, especially asthma, as well as the other diseases described herein.  
       SUMMARY OF THE INVENTION  
       [0006] This invention relates to ADAM family genes and other Interactor genes associated with asthma, and related diseases thereof. In specific embodiments, the invention relates to the ADAM and Interactor genes shown in Table 2, as well as complementary sequences, sequence variants, or fragments thereof, as described herein. The present invention also encompasses nucleic acid probes and primers useful for assaying a biological sample for the presence or expression of ADAM and Interactor genes. In particular, this invention relates to the use of ADAM family and Interactor genes for the treatment and prevention of asthma, and related diseases thereof.  
       [0007] The invention further encompasses novel nucleic acid variants comprising alleles or haplotypes of single nucleotide polymorphisms (SNPs) identified in several of the ADAM and Interactor genes. Nucleic acid variants comprising SNP alleles or haplotypes can be used to diagnose diseases such as asthma, or to determine a genetic predisposition thereto. In addition, the present invention encompasses nucleic acids comprising alternate splicing variants.  
       [0008] This invention also relates to vectors and host cells comprising ADAM and Interactor genes and nucleic acid sequences disclosed herein. Such vectors can be used for nucleic acid preparations, including antisense nucleic acids, and for the expression of encoded polypeptides or peptides. Host cells can be prokaryotic or eukaryotic cells. In specific embodiments, an expression vector comprises a DNA sequence encoding a known ADAM or Interactor gene, sequence variants, or fragments thereof, as described herein.  
       [0009] The present invention further relates to isolated ADAM or Interactor gene polypeptides and peptides. In specific embodiments, the polypeptides or peptides comprise the amino acid sequences encoded by the ADAM or Interactor gene sequence variants, or portions thereof, as described herein. In addition, this invention encompasses isolated fusion proteins comprising ADAM and Interactor polypeptides or peptides.  
       [0010] The present invention also relates to isolated antibodies, including monoclonal and polyclonal antibodies, and antibody fragments, that are specifically reactive with the ADAM and Interactor polypeptides, fusion proteins, variants, or portions thereof, as disclosed herein. In specific embodiments, monoclonal antibodies are prepared to be specifically reactive with a ADAM or Interactor polypeptides, peptides, or sequence variants thereof.  
       [0011] In addition, the present invention relates to methods of obtaining ADAM and Interactor polynucleotides and polypeptides, variant sequences, or fragments thereof, as disclosed herein. Also related are methods of obtaining antibodies and antibody fragments that bind to ADAM and Interactor polypeptides, variant sequences, or fragments thereof. The present invention also encompasses methods of obtaining ADAM and Interactor ligands, e.g., agonists, antagonists, inhibitors, and binding factors. Such ligands can be used as therapeutics for asthma and related diseases.  
       [0012] The present invention also relates to diagnostic methods and kits utilizing ADAM and Interactor (wild-type, mutant, or variant) nucleic acids, polypeptides, antibodies, or functional fragments thereof. Such factors can be used, for example, in diagnostic methods and kits for measuring expression levels or obtaining ADAM or Interactor gene expression, and to screen for various diseases, especially asthma. In addition, the ADAM and Interactor nucleic acids described herein can be used to identify chromosomal abnormalities correlating with asthma and other related diseases.  
       [0013] The present invention further relates to methods and therapeutics for the treatment of various diseases, including asthma, atopy, obesity, and inflammatory bowel disease. In various embodiments, therapeutics comprising the disclosed ADAM and Interactor gene nucleic acids, polypeptides, antibodies, ligands, variants, derivatives, or portions thereof, are administered to a subject to treat, prevent, or ameliorate such diseases. Specifically related are therapeutics comprising ADAM and Interactor gene antisense nucleic acids, monoclonal antibodies, and gene therapy vectors. Such therapeutics can be administered alone, or in combination with one or more disease treatments.  
       [0014] In addition, this invention relates to non-human transgenic animals and cell lines comprising one or more of the disclosed ADAM or Interactor gene nucleic acids, which can be used for drug screening, protein production, and other purposes. Also related are non-human knock-out animals and cell lines, wherein one or more endogenous ADAM or Interactor genes (i.e., orthologs), or portions thereof, are deleted or replaced by marker genes.  
       [0015] This invention further relates to methods of identifying ADAM and Interactor proteins that are candidates for being involved in asthma and related diseases (i.e., a “candidate protein”). Such proteins are identified by a method comprising: 1) identifying a protein in a first individual having the asthma phenotype; 2) identifying an ADAM-related or Interactor protein in a second individual not having the asthma phenotype; and 3) comparing the protein of the first individual to the protein(s) of the second individual, wherein a) the protein that is present in the second individual but not the first individual is the candidate protein; or b) the protein that is present in a higher amount in the second individual than in the first individual is the candidate protein; or c) the protein that is present in a lower amount in the second individual than in the first individual is the candidate protein. 
     
    
    
     BRIEF DESCRIPTION OF THE FIGURES  
     [0016]FIG. 1 shows the cDNA sequence for Gene 803 splice variant 1 (Accession No. NM — 003025) with the SNPs underlined.  
     [0017]FIG. 2 shows the cDNA sequence for Gene 803 splice variant 2 (Accession No. AK — 097616) with the SNPs underlined.  
     [0018]FIG. 3 shows the cDNA sequence of Gene 845 (Accession No. NM — 023038) with the SNPs underlined.  
     [0019]FIG. 4 shows the cDNA sequence for Gene 847 splice variant 1 (Accession No. NM — 004883) with the SNPs underlined.  
     [0020]FIG. 5 shows the cDNA sequence for Gene 847 splice variant 2 (Accession No. NM — 013981) with the SNPs underlined.  
     [0021]FIG. 6 shows the cDNA sequence for Gene 847 splice variant 3 (Accession No. NM — 013982) with the SNPs underlined.  
     [0022]FIG. 7 shows the cDNA sequence for Gene 847 splice variant 4 (Accession No. NM — 013983) with the SNPs underlined.  
     [0023]FIG. 8 shows the cDNA sequence for Gene 847 splice variant 5 (Accession No. NM — 013984) with the SNPs underlined.  
     [0024]FIG. 9 shows the cDNA sequence for Gene 847 splice variant 6 (Accession No. NM — 013985) with the SNPs underlined.  
     [0025]FIG. 10 shows the cDNA sequence for Gene 874 (Accession No. NM — 003026) with the SNPs underlined.  
     [0026]FIG. 11 shows the cDNA sequence for Gene 962 splice variant 1 (Accession No. NM — 014244) with the SNPs underlined.  
     [0027]FIG. 12 shows the cDNA sequence for Gene 962 splice variant 2 (Accession No. NM — 021599) with the SNPs underlined. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0028] This invention is based on the discovery that ADAM genes and Interactor genes are associated with various diseases, including asthma, atopy, inflammatory bowel disease, and obesity.  
     [0029] To aid in the understanding of the specification and claims, the following definitions are provided.  
     DEFINITIONS  
     [0030] “ADAM genes” or “ADAM family genes” or “ADAM-related genes” refers to the zinc-dependent metalloprotease gene superfamily comprised of multiple subgroups. Currently, there are 33 members of the ADAM family. The ADAM genes encode proteins of approximately 750 amino acids with 8 different domains. Domain I is a pre-domain and contains the signal sequence peptide that facilitates secretion through the plasma membrane. Domain II is a pro-domain that is cleaved before the protein is secreted resulting in activation of the catalytic domain. Domain III is a catalytic domain containing metalloprotease activity. Domain IV is a disintegrin-like domain and is believed to interact with integrins or other receptors. Domain V is a cysteine-rich domain and is speculated to be involved in protein-protein interactions or in the presentation of the disintegrin-like domain. Domain VI is an EGF-like domain that plays a role in stimulating membrane fusion. Domain VII is a transmembrane domain that anchors the ADAM protein to the membrane. Domain VIII is a cytoplasmic domain and contains binding sites for cytoskeletal-associated proteins and SH3 binding domains that may play a role in bi-directional signaling.  
     [0031] “Interactor genes” or “Interactors” refer to genes or proteins whose members interact with, are ligands or substrates for, or otherwise act in concert with ADAM family genes in the cellular processes or pathways associated with the diseases described herein. Examples of Interactor genes include those shown in Table 2, such as the Neuregulin and Endophilin family genes.  
     [0032] “Disorder region” refers to a portion of the human chromosome correlated with the disease type. A “disorder-associated” nucleic acid or “disorder-associated” polypeptide sequence refers to a nucleic acid sequence that maps to the disorder region and polypeptides encoded thereby. For nucleic acid sequences, this encompasses sequences that are homologous or complementary to the reference sequence, as well as “sequence-conservative variants” and “function-conservative variants.” For polypeptide sequences, this encompasses “function-conservative variants.” Also encompassed are naturally occurring mutations associated with respiratory diseases including, but not limited to, asthma and atopy, as well as other diseases arising from mutations in this region including those described in detail herein. These mutations are not limited to mutations that cause inappropriate expression (e.g., lack of expression, over-expression, and expression in an inappropriate tissue type).  
     [0033] The term “SNP” as used herein refers to a site in a nucleic acid sequence that contains a nucleotide polymorphism. In accordance with this invention, a SNP may comprise one of two possible “alleles”. For example SNP E+1 may comprise allele C or T (Table 5, below). Thus, a nucleic acid molecule comprising SNP E+1 may include a C or T at the polymorphic position. For a combination of SNPs, the term “haplotype” is used. As an example, the haplotype A/C is observed for SNP combination G1/V−1 (Table 24, below). Thus, A is present at the polymorphic position in SNP G1 and C is present in the polymorphic position in SNP V−1. It should be noted that haplotype representation “A/C” does not indicate “A or C”. Instead, the haplotype representation “A/C” indicates that both the A allele and the C allele are present in their respective SNPs. In addition, the SNP representation “G1/V−1” does not indicate “G1 or V−1”. Instead, “G1/V−1” indicates that both SNPs are present. In some instances, a specific allele or haplotype may be associated with susceptibility to a disease or condition of interest, e.g. asthma. In other instances, an allele or haplotype may be associated with a decrease in susceptibility to a disease or condition of interest, i.e., a protective sequence.  
     [0034] “Sequence-conservative” variants are those in which a change of one or more nucleotides in a given codon position results in no alteration in the amino acid encoded at that position (i.e., silent mutations). “Function-conservative” variants are those in which a change in one or more nucleotides in a given codon position results in a polypeptide sequence in which a given amino acid residue in a polypeptide has been changed without substantially altering the overall conformation and function of the native polypeptide, including, but not limited to, replacement of an amino acid with one having similar physico-chemical properties (such as, for example, acidic, basic, hydrophobic, and the like). “Function-conservative” variants also include analogs of a given polypeptide and any polypeptides that have the ability to elicit antibodies specific to a designated polypeptide.  
     [0035] “Nucleic acid or “polynucleotide” as used herein refers to purine- and pyrimidine-containing polymers of any length, either polyribonucleotides or polydeoxyribonucleotide or mixed polyribo-polydeoxyribonucleotides. This includes single-and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleic acids” (PNA) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing modified bases.  
     [0036] A “coding sequence” or a “protein-coding sequence” is a polynucleotide sequence capable of being transcribed into mRNA and capable of being translated into a polypeptide. The boundaries of the coding sequence are typically determined by a translation start codon at the 5′-terminus and a translation stop codon at the 3′-terminus.  
     [0037] As used herein, the “reference sequence” refers to the sequence used to compare individuals in identifying single nucleotide polymorphisms and the like. Reference sequences may be referred to herein by their GenBank Accession number, GeneBank Protein Accession number, GeneBank Genomic Contig Accession number, Genebank Genomic Clone Accession number, or by specific markers. “Variant” sequences refer to nucleotide sequences (and in some cases, the encoded amino acid sequences) that differ from the reference sequence(s) at one or more positions. Non-limiting examples of variant sequences include the disclosed single nucleotide polymorphisms (SNPs), including SNP alleles and haplotypes, alternate splice variants, and the amino acid sequences encoded by these variants.  
     [0038] “Expressed Sequence Tag (EST)” is a nucleic acid that encodes for a portion of or a full-length protein sequence.  
     [0039] A “complement” of a nucleic acid sequence as used herein refers to the “antisense” sequence that participates in Watson-Crick base-pairing with the original sequence.  
     [0040] A “probe” refers to a nucleic acid or oligonucleotide that forms a hybrid structure with a sequence in a target region due to complementarily of at least one sequence in the probe with a sequence in the target region.  
     [0041] Nucleic acids are “hybridizable” to each other when at least one strand of nucleic acid can anneal to another nucleic acid strand under defined stringency conditions. As is well known in the art, stringency of hybridization is determined, e.g., by (a) the temperature at which hybridization and washing is performed, and (b) the ionic strength and polarity (e.g., formamide) of the hybridization and washing solutions, as well as other parameters. Hybridization requires that the two nucleic acids contain substantially complementary sequences; depending on the stringency of hybridization, however, mismatches may be tolerated. The appropriate stringency for hybridizing nucleic acids depends on the length of the nucleic acids and the degree of complementarily, variables well known in the art.  
     [0042] “Gene” refers to a DNA sequence that encodes through its template or messenger RNA a sequence of amino acids characteristic of a specific peptide, polypeptide, or protein. The term “gene” as used herein with reference to genomic DNA includes intervening, non-coding regions, as well as regulatory regions, and can include 5′ and 3′ ends.  
     [0043] “Gene sequence” refers to a DNA molecule, including a DNA molecule that contains a non-transcribed or non-translated sequence. The term is also intended to include any combination of gene(s), gene fragment(s), non-transcribed sequence(s), or non-translated sequence(s) that are present on the same DNA molecule.  
     [0044] A gene sequence is “wild-type” if such sequence is usually found in individuals unaffected by the disease or condition of interest. However, environmental factors and other genes can also play an important role in the ultimate determination of the disease. In the context of complex diseases involving multiple genes (“oligogenic disease”), the “wild type”, or normal sequence can also be associated with a measurable risk or susceptibility, receiving its reference status based on its frequency in the general population. As used herein, “wild-type” refers to the reference sequence. The wild-type sequences are used to identify the variants (single nucleotide polymorphisms) described in detail herein.  
     [0045] A gene sequence is a “mutant” sequence if it differs from the wild-type sequence. For example, an ADAM-related gene nucleic acid sequence containing a single nucleotide polymorphism is a mutant sequence. In some cases, the individual carrying such genes has increased susceptibility toward the disease or condition of interest. In other cases, the “mutant” sequence might also refer to a sequence that decreases the susceptibilty toward a disease or condition of interest, and thus acting in a protective manner. Also a gene is a “mutant” gene if too much (“overexpressed”) or too little (“underexpressed”) of such gene is expressed in the tissues in which such gene is normally expressed, thereby causing the disease or condition of interest.  
     [0046] “cDNA” refers to complementary or copy DNA produced from an RNA template by the action of RNA-dependent DNA polymerase (reverse transcriptase). Thus, a “cDNA clone” means a duplex DNA sequence complementary to an RNA molecule of interest, carried in a cloning vector or PCR amplified. This term includes genes from which the intervening sequences have been removed.  
     [0047] “Recombinant DNA” means a molecule that has been recombined by in vitro splicing/and includes cDNA or a genomic DNA sequence.  
     [0048] “Cloning” refers to the use of in vitro recombination techniques to insert a particular gene or other DNA sequence into a vector molecule. In order to successfully clone a desired gene, it is necessary to use methods for generating DNA fragments, for joining the fragments to vector molecules, for introducing the composite DNA molecule into a host cell in which it can replicate, and for selecting the clone having the target gene from amongst the recipient host cells.  
     [0049] “cDNA library” refers to a collection of recombinant DNA molecules containing cDNA inserts, which together comprise the entire genome of an organism. Such a cDNA library can be prepared by methods known to one skilled in the art and described by, for example, Cowell and Austin, 1997, “cDNA Library Protocols,” Methods in Molecular Biology. Generally, RNA is first isolated from the cells of an organism from whose genome it is desired to clone a particular gene.  
     [0050] The term “vector” as used herein refers to a nucleic acid molecule capable of replicating another nucleic acid to which it has been linked. A vector, for example, can be a plasmid.  
     [0051] “Cloning vector” refers to a plasmid or phage DNA or other DNA sequence that is able to replicate in a host cell. The cloning vector is characterized by one or more endonuclease recognition sites at which such DNA sequences may be cut in a determinable fashion without loss of an essential biological function of the DNA, which may contain a marker suitable for use in the identification of transformed cells.  
     [0052] “Expression vector” refers to a vehicle or vector similar to a cloning vector but which is capable of expressing a nucleic acid sequence that has been cloned into it, after transformation into a host. A nucleic acid sequence is “expressed” when it is transcribed to yield an mRNA sequence. In most cases, this transcript will be translated to yield amino acid sequence. The cloned gene is usually placed under the control of (i.e., operably linked to) an expression control sequence.  
     [0053] “Expression control sequence” or “regulatory sequence” refers to a nucleotide sequence that controls or regulates expression of structural genes when operably linked to those genes. These include, for example, the lac systems, the trp system, major operator and promoter regions of the phage lambda, the control region of fd coat protein and other sequences known to control the expression of genes in prokaryotic or eukaryotic cells. Expression control sequences will vary depending on whether the vector is designed to express the operably linked gene in a prokaryotic or eukaryotic host, and may contain transcriptional elements such as enhancer elements, termination sequences, tissue-specificity elements or translational initiation and termination sites.  
     [0054] “Operably linked” means that the promoter controls the initiation of expression of the gene. A promoter is operably linked to a sequence of proximal DNA if upon introduction into a host cell the promoter determines the transcription of the proximal DNA sequence(s) into one or more species of RNA. A promoter is operably linked to a DNA sequence if the promoter is capable of initiating transcription of that DNA sequence.  
     [0055] “Host” includes prokaryotes and eukaryotes. The term includes an organism or cell that is the recipient of a replicable expression vector.  
     [0056] The introduction of the nucleic acids into the host cell by any method known in the art, including those described herein, will be referred to herein as “transformation.” The cells into which have been introduced nucleic acids described above are meant to also include the progeny of such cells.  
     [0057] “Amplification of nucleic acids” refers to methods such as polymerase chain reaction (PCR), ligation amplification (or ligase chain reaction, LCR) and amplification methods based on the use of Q-beta replicase. These methods are well known in the art and described, for example, in U.S. Pat. Nos. 4,683,195 and 4,683,202. Reagents and hardware for conducting PCR are commercially available. Primers useful for amplifying sequences from the disorder region are preferably complementary to, and preferably hybridize specifically to, sequences in the disorder region_or in regions that flank a target region therein. Genes generated by amplification may be sequenced directly. Alternatively, the amplified sequence(s) may be cloned prior to sequence analysis.  
     [0058] A nucleic acid or fragment thereof is “substantially homologous” or “substantially similar” to another if, when optimally aligned (with appropriate nucleotide insertions or deletions) with the other nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least 60% of the nucleotide bases, usually at least 70%, more usually at least 80%, preferably at least 90%, and more preferably at least 95-98% of the nucleotide bases.  
     [0059] Alternatively, substantial homology or similarity exists when a nucleic acid or fragment thereof will hybridize, under selective hybridization conditions, to another nucleic acid (or a complementary strand thereof). Selectivity of hybridization exists when hybridization which is substantially more selective than total lack of specificity occurs. Typically, selective hybridization will occur when there is at least 55% homology over a stretch of at least nine or more nucleotides, preferably at least 65%, more preferably at least 75%, and most preferably at least 90% (see, M. Kanehisa, 1984,  Nucl. Acids Res.  11:203-213). The length of homology comparison, as described, may be over longer stretches, and in certain embodiments will often be over a stretch of at least 14 nucleotides, usually at least 20 nucleotides, more usually at least 24 nucleotides, typically at least 28 nucleotides, more typically at least 32 nucleotides, and preferably at least 36 or more nucleotides.  
     [0060] Nucleic acids referred to herein as “isolated” are nucleic acids separated away from the nucleic acids of the genomic DNA or cellular RNA of their source of origin (e.g., as it exists in cells or in a mixture of nucleic acids such as a library), and may have undergone further processing. “Isolated”, as used herein, refers to nucleic or amino acid sequences that are at least 60% free, preferably 75% free, and most preferably 90% free from other components with which they are naturally associated. “Isolated” nucleic acids (polynucleotides) include nucleic acids obtained by methods described herein, similar methods or other suitable methods, including essentially pure nucleic acids, nucleic acids produced by chemical synthesis, by combinations of biological and chemical methods, and recombinant nucleic acids which are isolated. Nucleic acids referred to herein as “recombinant” are nucleic acids which have been produced by recombinant DNA methodology, including those nucleic acids that are generated by procedures which rely upon a method of artificial replication, such as the polymerase chain reaction (PCR) or cloning into a vector using restriction enzymes. “Recombinant” nucleic acids are also those that result from recombination events that occur through the natural mechanisms of cells, but are selected for after the introduction to the cells of nucleic acids designed to allow or make probable a desired recombination event. Portions of the isolated nucleic acids which code for polypeptides having a certain function can be identified and isolated by, for example, the method of Jasin, M., et al., U.S. Pat. No. 4,952,501.  
     [0061] In the context of this invention, the term “oligonucleotide” refers to naturally occurring species or synthetic species formed from naturally occurring subunits or their close homologs. The term may also refer to moieties that function similarly to oligonucleotides, but have non-naturally-occurring portions. Thus, oligonucleotides may have altered sugar moieties or inter-sugar linkages. Exemplary among these are phosphorothioate and other sulfur containing species which are known in the art.  
     [0062] As used herein, the terms “protein” and “polypeptide” are synonymous. “Peptides” are defined as fragments or portions of polypeptides, preferably fragments or portions having at least one functional activity (e.g., proteolysis, adhesion, fusion, antigenic, or intracellular activity) as the complete polypeptide sequence.  
     [0063] As used herein, “isolated” proteins or polypeptides are proteins or polypeptides purified to a state beyond that in which they exist in cells. In a preferred embodiment, they are at least 10% pure; i.e., most preferably they are substantially purified to 80 or 90% purity. “Isolated” proteins or polypeptides include proteins or polypeptides obtained by methods described infra, similar methods or other suitable methods, and include essentially pure proteins or polypeptides, proteins or polypeptides produced by chemical synthesis or by combinations of biological and chemical methods, and recombinant proteins or polypeptides which are isolated. Proteins or polypeptides referred to herein as “recombinant” are proteins or polypeptides produced by the expression of recombinant nucleic acids.  
     [0064] A “portion” as used herein with regard to a protein or polypeptide, refers to fragments of that protein or polypeptide. The fragments can range in size from 5 amino acid residues to all but one residue of the entire protein sequence. Thus, a portion or fragment can be at least 5, 5-50, 50-100, 100-200, 200-400, 400-800, or more consecutive amino acid residues of a protein or polypeptide, or variants thereof.  
     [0065] The term “immunogenic”, refers to the ability of a molecule (e.g., a polypeptide or peptide) to elicit a humoral or cellular immune response in a host animal.  
     [0066] The term “antigenic” refers to the ability of a molecule (e.g., a polypeptide or peptide) to bind to its specific antibody with sufficiently high affinity to form a detectable antigen-antibody complex.  
     [0067] “Antibodies” refer to polyclonal and monoclonal antibodies and fragments thereof, and immunologic binding equivalents thereof, that can bind to asthma proteins and fragments thereof or to nucleic acid sequences of ADAM-related or Interactor genes, particularly from chromosomal regions associated with asthma or a portion thereof. The term antibody is used both to refer to a homogeneous molecular entity, or a mixture such as a serum product made up of a plurality of different molecular entities.  
     [0068] The term “monoclonal antibody” or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of a ADAM or Interactor polypeptide or peptide. A monoclonal antibody composition thus typically displays a single binding affinity for a particular ADAM or Interactor polypeptide or peptide with which it immunoreacts.  
     [0069] The term “ligand” as used herein describes any molecule, protein, peptide, or compound with the capability of directly or indirectly altering the physiological function, stability, or levels of a polypeptide.  
     [0070] A “sample” as used herein refers to a biological sample, such as, for example, tissue or fluid isolated from an individual (including, without limitation, plasma, serum, cerebrospinal fluid, lymph, tears, saliva, milk, pus, and tissue exudates and secretions) or from in vitro cell culture constituents, as well as samples obtained from, for example, a laboratory procedure.  
     [0071] As used herein, the term “ortholog” denotes a gene or polypeptide obtained from one species that has homology to an analogous gene or polypeptide from a different species. This is in contrast to “paralog”, which denotes a gene or polypeptide obtained from a given species that has homology to a distinct gene or polypeptide from that same species.  
     [0072] Standard reference works setting forth the general principles of recombinant DNA technology include J. Sambrook et al., 1989,  Molecular Cloning: A Laboratory Manual,  2d Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; P. B. Kaufman et al., (eds), 1995,  Handbook of Molecular and Cellular Methods in Biology and Medicine,  CRC Press, Boca Raton; M. J. McPherson (ed), 1991,  Directed Mutagenesis: A Practical Approach,  IRL Press, Oxford; J. Jones, 1992,  Amino Acid and Peptide Synthesis,  Oxford Science Publications, Oxford; B. M. Austen and O. M. R. Westwood, 1991,  Protein Targeting and Secretion,  IRL Press, Oxford; D. N Glover (ed), 1985,  DNA Cloning,  Volumes I and II; M. J. Gait (ed), 1984,  Oligonucleotide Synthesis;  B. D. Hames and S. J. Higgins (eds), 1984,  Nucleic Acid Hybridization;  Wu and Grossman (eds),  Methods in Enzymoloqy  (Academic Press, Inc.), Vol. 154 and Vol. 155; Quirke and Taylor (eds), 1991,  PCR - A Practical Approach;  Hames and Higgins (eds), 1984,  Transcription and Translation;  R. I. Freshney (ed), 1986,  Animal Cell Culture; Immobilized Cells and Enzymes,  1986, IRL Press; Perbal, 1984,  A Practical Guide to Molecular Cloning;  J. H. Miller and M. P. Calos (eds), 1987,  Gene Transfer Vectors for Mammalian Cells,  Cold Spring Harbor Laboratory Press; M. J. Bishop (ed), 1998,  Guide to Human Genome Computing,  2d Ed., Academic Press, San Diego, Calif.; L. F. Peruski and A. H. Peruski, 1997,  The Internet and the New Biology: Tools for Genomic and Molecular Research,  American Society for Microbiology, Washington, D.C.  
     [0073] Standard reference works setting forth the general principles of immunology include S. Sell, 1996,  Immunology, Immunopathology  &amp;  Immunity,  5th Ed., Appleton &amp; Lange, Publ., Stamford, Conn.; D. Male et al., 1996,  Advanced Immunology,  3d Ed., Times Mirror Int&#39;l Publishers Ltd., Publ., London; D. P. Stites and A. I. Terr, 1991,  Basic and Clinical Immunology,  7th Ed., Appleton &amp; Lange, Publ., Norwalk, Conn.; and A. K. Abbas et al., 1991,  Cellular and Molecular Immunology,  W. B. Saunders Co., Publ., Philadelphia, Pa. Any suitable materials and methods known to those of skill can be utilized in carrying out the present invention; however, preferred materials and methods are described. Materials, reagents, and the like to which reference is made in the following description and examples are generally obtainable from commercial sources, and specific vendors are cited herein.  
     NUCLEIC ACIDS  
     [0074] The present invention relates to nucleic acids from ADAM and Interactor genes. In a specific embodiment, the invention relates to ADAM and Interactor nucleic acid sequences shown in column 4 of Table 2. RNA, fragments of the genomic, cDNA, or RNA nucleic acids comprising 20, 40, 60, 100, 200, 500 or more contiguous nucleotides, and the complements thereof. Closely related variants are also included as part of this invention, as well as recombinant nucleic acids comprising at least 50, 60, 70, 80, or 90% of the nucleic acids described above which would be identical to nucleic acids from ADAM and Interactor genes except for one or a few substitutions, deletions, or additions.  
     [0075] Further, the nucleic acids of this invention include the adjacent chromosomal regions of ADAM or Interactor genes required for accurate expression of the respective gene. In one embodiment, the present invention is directed to at least 15 contiguous nucleotides of the nucleic acid sequence of any of the sequences shown in column 4 of Table 2, SEQ ID NOs. 1-9, and FIGS.  1 - 12 . More particularly, embodiments of this invention include BAC clones of the nucleic acid sequences of the invention.  
     [0076] The invention also relates to direct selected clones and EST&#39;s from ADAM and Interactor genes. In a preferred embodiment, the invention relates to clusters of nucleic acids combining the direct selected clones with EST&#39;s homologous to BAC sequences and BAC end sequences.  
     [0077] The invention also concerns the use of the nucleotide sequence of the nucleic acids of this invention to identify DNA probes for ADAM and Interactor genes, BAC end sequences, BACs, direct selected clones, and sequence clusters, PCR primers to amplify the ADAM and Interactor genes, nucleotide polymorphisms, and regulatory elements of the ADAM family and interactor genes.  
     [0078] This invention further relates to methods of using isolated or recombinant ADAM and Interactor gene sequences (DNA or RNA) that are characterized by their ability to hybridize to (a) a nucleic acid encoding a protein or polypeptide, such as a nucleic acid having any of the sequences shown in column 4 of Table 2, or (b) a fragment of the foregoing. For example, a fragment can comprise the minimum nucleotides of an ADAM or Interactor protein required to encode a functional ADAM or Interactor protein, or the minimum nucleotides to encode a polypeptide, or to encode a functional equivalent thereof. A functional equivalent can include a polypeptide, which, when incorporated into a cell, has all or part of the activity of an ADAM or Interactor protein. A functional equivalent of an ADAM or Interactor protein, therefore, would have a similar amino acid sequence (at least 65% sequence identity) and similar characteristics to, or perform in substantially the same way as an ADAM or Interactor protein. A nucleic acid which hybridizes to a nucleic acid encoding an ADAM or Interactor protein or polypeptide can be double- or single-stranded. Hybridization to DNA, such as DNA having a sequence set forth in Tables 2-5 and 7, includes hybridization to the strand shown, or to the complementary strand.  
     [0079] The sequences of the present invention may be derived from a variety of sources including DNA, cDNA, synthetic DNA, synthetic RNA, or combinations thereof. Such sequences may comprise genomic DNA, which may or may not include naturally occurring introns. Moreover, such genomic DNA may be obtained in association with promoter regions or poly (A) sequences. The sequences, genomic DNA, or cDNA may be obtained in any of several ways. Genomic DNA can be extracted and purified from suitable cells by means well known in the art. Alternatively, mRNA can be isolated from a cell and used to produce cDNA by reverse transcription or other means.  
     [0080] The present invention also relates to nucleic acids that encode a polypeptide having the amino acid sequence shown in column 5 of Table 2, or functional equivalents thereof. A functional equivalent of an ADAM or Interactor protein includes fragments or variants that perform at least one characteristic function of the ADAM or Interactor protein (e.g., antigenic or intracellular activity). Preferably, a functional equivalent will share at least 65% sequence identity with the ADAM or Interactor polypeptide.  
     [0081] Sequence identity calculations can be performed using computer programs, hybridization methods, or calculations. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, the GCG program package, BLASTN, BLASTX, TBLASTX, and FASTA (J. Devereux et al., 1984,  Nucleic Acids Research  12(1):387; S. F. Altschul et al., 1990,  J. Molec. Biol.  215:403-410; W. Gish and D. J. States, 1994,  Nature Genet.  3:266-272; W. R. Pearson and D. J. Lipman, 1988,  Proc Natl. Acad. Sci. USA  85(8):2444-8). The BLAST programs are publicly available from NCBI and other sources. The well-known Smith Waterman algorithm may also be used to determine identity.  
     [0082] For example, nucleotide sequence identity can be determined by comparing a query sequences to sequences in publicly available sequence databases (NCBI) using the BLASTN2 algorithm (S. F. Altschul et al., 1997,  Nucl. Acids Res.,  25:3389-3402). The parameters for a typical search are: E=0.05, v=50, B=50, wherein E is the expected probability score cutoff, V is the number of database entries returned in the reporting of the results, and B is the number of sequence alignments returned in the reporting of the results (S. F Altschul et al., 1990,  J. Mol. Biol.,  215:403-410).  
     [0083] In another approach, nucleotide sequence identity can be calculated using the following equation: % identity=(number of identical nucleotides)/(alignment length in nucleotides)*100. For this calculation, alignment length includes internal gaps but not includes terminal gaps. Alternatively, nucleotide sequence identity can be determined experimentally using the specific hybridization conditions described below.  
     [0084] In accordance with the present invention, polynucleotide alterations are selected from the group consisting of at least one nucleotide deletion, substitution, including transition and transversion, insertion, or modification (e.g., via RNA or DNA analogs). Alterations may occur at the 5′ or 3′ terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among the nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence. Alterations of a polynucleotide sequence of any one of the sequences shown in Table 2 may create nonsense, missense, or frameshift mutations in this coding sequence, and thereby alter the polypeptide encoded by the polynucleotide following such alterations.  
     [0085] Such altered nucleic acids, including DNA or RNA, can be detected and isolated by hybridization under high stringency conditions or moderate stringency conditions, for example, which are chosen to prevent hybridization of nucleic acids having non-complementary sequences. “Stringency conditions” for hybridizations is a term of art that refers to the conditions of temperature and buffer concentration that permit hybridization of a particular nucleic acid to another nucleic acid in which the first nucleic acid may be perfectly complementary to the second, or the first and second may share some degree of complementarity that is less than perfect.  
     [0086] For example, certain high stringency conditions can be used which distinguish perfectly complementary nucleic acids from those of less complementarity. “High stringency conditions” and “moderate stringency conditions” for nucleic acid hybridizations are explained in F. M. Ausubel et al. (eds), 1995,  Current Protocols in Molecular Biology,  John Wiley and Sons, Inc., New York, N.Y., the teachings of which are hereby incorporated by reference. In particular, see pages 2.10.1-2.10.16 (especially pages 2.10.8-2.10.11) and pages 6.3.1-6.3.6. The exact conditions which determine the stringency of hybridization depend not only on ionic strength, temperature and the concentration of destabilizing agents such as formamide, but also on factors such as the length of the nucleic acid sequence, base composition, percent mismatch between hybridizing sequences and the frequency of occurrence of subsets of that sequence within other non-identical sequences. Thus, high or moderate stringency conditions can be determined empirically.  
     [0087] By varying hybridization conditions from a level of stringency at which no hybridization occurs to a level at which hybridization is first observed, conditions which will allow a given sequence to hybridize with the most similar sequences in the sample can be determined. Preferably the hybridizing sequences will have 60-70% sequence identity, more preferably 70-85% sequence identity, and even more preferably 90-100% sequence identity.  
     [0088] Typically, the hybridization reaction is initially performed under conditions of low stringency, followed by washes of varying, but higher stringency. Reference to hybridization stringency, e.g., high, moderate, or low stringency, typically relates to such washing conditions. Hybridization conditions are based on the melting temperature (T m ) of the nucleic acid probe or primer and are typically classified by degree of stringency of the conditions under which hybridization is measured (Ausubel et al., 1995). For example, high stringency hybridization typically occurs at about 5-10% C. below the T m ; moderate stringency hybridization occurs at about 10-20% below the T m ; and low stringency hybridization occurs at about 20-25% below the T m . The melting temperature can be approximated by the formulas as known in the art, depending on a number of parameters, such as the length of the hybrid or probe in number of nucleotides, or hybridization buffer ingredients and conditions. As a general guide, T m  decreases approximately 1° C. with every 1% decrease in sequence identity at any given SSC concentration. Generally, doubling the concentration of SSC results in an increase in T m  of ˜17° C. Using these guidelines, the washing temperature can be determined empirically for moderate or low stringency, depending on the level of mismatch sought.  
     [0089] High stringency hybridization conditions are typically carried out at 65 to 68° C. in 0.1×SSC and 0.1% SDS. Highly stringent conditions allow hybridization of nucleic acid molecules having about 95 to 100% sequence identity. Moderate stringency hybridization conditions are typically carried out at 50 to 65° C. in 1×SSC and 0.1% SDS. Moderate stringency conditions allow hybridization of sequences having at least 80 to 95% nucleotide sequence identity. Low stringency hybridization conditions are typically carried out at 40 to 50° C. in 6×SSC and 0.1% SDS. Low stringency hybridization conditions allow detection of specific hybridization of nucleic acid molecules having at least 50 to 80% nucleotide sequence identity.  
     [0090] For example, high stringency conditions can be attained by hybridization in 50% formamide, 5× Denhardt&#39;s solution, 5×SSPE or SSC (1×SSPE buffer comprises 0.15 M NaCl, 10 mM Na 2 HPO 4 , 1 mM EDTA; 1×SSC buffer comprises 150 mM NaCl, 15 mM sodium citrate, pH 7.0), 0.2% SDS at about 42° C., followed by washing in 1×SSPE or SSC and 0.1% SDS at a temperature of at least 42° C., preferably about 55° C., more preferably about 65° C. Moderate stringency conditions can be attained, for example, by hybridization in 50% formamide, 5× Denhardt&#39;s solution, 5×SSPE or SSC, and 0.2% SDS at 42° C. to about 50° C., followed by washing in 0.2×SSPE or SSC and 0.2% SDS at a temperature of at least 42° C., preferably about 55° C., more preferably about 65° C. Low stringency conditions can be attained, for example, by hybridization in 10% formamide, 5× Denhardt&#39;s solution, 6×SSPE or SSC, and 0.2% SDS at 42° C., followed by washing in 1×SSPE or SSC, and 0.2% SDS at a temperature of about 45° C., preferably about 50° C. in 4×SSC at 60° C. for 30 min.  
     [0091] High stringency hybridization procedures typically (1) employ low ionic strength and high temperature for washing, such as 0.015 M NaCl/0.0015 M sodium citrate, pH 7.0 (0.1×SSC) with 0.1% sodium dodecyl sulfate (SDS) at 50° C.; (2) employ during hybridization 50% (vol/vol) formamide with 5× Denhardt&#39;s solution (0.1% weight/volume highly purified bovine serum albumin/0.1% wt/vol Ficoll/0.1% wt/vol polyvinylpyrrolidone), 50 mM sodium phosphate buffer at pH 6.5 and 5×SSC at 42° C.; or (3) employ hybridization with 50% formamide, 5×SSC, 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt&#39;s solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC and 0.1% SDS.  
     [0092] In one particular embodiment, high stringency hybridization conditions may be attained by:  
     [0093] Prehybridization treatment of the support (e.g., nitrocellulose filter or nylon membrane), to which is bound the nucleic acid capable of hybridizing with any of the sequences of the invention, is carried out at 65° C. for 6 hr with a solution having the following composition: 4×SSC, 10× Denhardt&#39;s (1× Denhardt&#39;s comprises 1% Ficoll, 1% polyvinylpyrrolidone, 1% BSA (bovine serum albumin); 1×SSC comprises of 0.15 M of NaCl and 0.015 M of sodium citrate, pH 7);  
     [0094] Replacement of the pre-hybridization solution in contact with the support by a buffer solution having the following composition: 4×SSC, 1× Denhardt&#39;s, 25 mM NaPO 4 , pH 7, 2 mM EDTA, 0.5% SDS, 100 μg/ml of sonicated salmon sperm DNA containing a nucleic acid derived from the sequences of the invention as probe, in particular a radioactive probe, and previously denatured by a treatment at 100° C. for 3 min;  
     [0095] Incubation for 12 hr at 65° C.;  
     [0096] Successive washings with the following solutions: 1) four washings with 2×SSC, 1× Denhardt&#39;s, 0.5% SDS for 45 min at 65° C.; 2) two washings with 0.2×SSC, 0.1×SSC for 45 min at 65° C.; and 3) 0.1×SSC, 0.1% SDS for 45 min at 65° C.  
     [0097] Additional examples of high, medium, and low stringency conditions can be found in Sambrook et al., 1989. Exemplary conditions are also described in M. H. Krause and S. A. Aaronson, 1991,  Methods in Enzymology,  200:546-556; Ausubel et al., 1995. It is to be understood that the low, moderate and high stringency hybridization/washing conditions may be varied using a variety of ingredients, buffers, and temperatures well known to and practiced by the skilled practitioner.  
     [0098] Isolated or recombinant nucleic acids that are characterized by their ability to hybridize to a) a nucleic acid encoding an ADAM or Interactor polypeptide, such as the nucleic acids depicted in column 4 of Table 2, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ; b) the complement of (a); c) or a portion of (a) or (b) (e.g., under high or moderate stringency conditions), may further encode a protein or polypeptide having at least one function characteristic of an ADAM or Interactor polypeptide, or binding of antibodies that also bind to non-recombinant ADAM or Interactor proteins or polypeptides. The catalytic or binding function of a protein or polypeptide encoded by the hybridizing nucleic acid may be detected by standard enzymatic assays for activity or binding (e.g., assays that measure the binding of a transit peptide or a precursor, or other components of the translocation machinery). Enzymatic assays, complementation tests, or other suitable methods can also be used in procedures for the identification and isolation of nucleic acids which encode a polypeptide such as a polypeptide of the amino acid sequences shown in column 5 of Table 2, or a functional equivalent of these polypeptides. The antigenic properties of proteins or polypeptides encoded by hybridizing nucleic acids can be determined by immunological methods employing antibodies that bind to an ADAM or Interactor polypeptide such as immunoblot, immunoprecipitation and radioimmunoassay. PCR methodology, including RAGE (Rapid Amplification of Genomic DNA Ends), can also be used to screen for and detect the presence of nucleic acids which encode ADAM or Interactor-like proteins and polypeptides, and to assist in cloning such nucleic acids from genomic DNA. PCR methods for these purposes can be found in Innis, M. A., et al., 1990,  PCR Protocols: A Guide to Methods and Applications,  Academic Press, Inc., San Diego, Calif., incorporated herein by reference.  
     [0099] It is understood that, as a result of the degeneracy of the genetic code, many nucleic acid sequences are possible which encode ADAM or Interactor gene-like proteins or polypeptides. Some of these will have little homology to the nucleotide sequences of any known or naturally-occurring ADAM or Interactor genes but can be used to produce the proteins and polypeptides of this invention by selection of combinations of nucleotide triplets based on codon choices. Such variants, while not hybridizable to a naturally occurring ADAM or Interactor gene, are contemplated within this invention.  
     [0100] Also encompassed by the present invention are alternate splice variants produced by differential processing of the primary transcript(s) of ADAM or Interactor genomic DNA. An alternate splice variant may comprise, for example, the sequences shown in Table 2 or FIGS.  1 - 12 . Alternate splice variants can also comprise other combinations of introns/exons of ADAM or Interactor genes, which can be determined by those of skill in the art. Alternate splice variants can be determined experimentally, for example, by isolating and analyzing cellular RNAs (e.g., Southern blotting or PCR), or by screening cDNA libraries using the 12q23-qter nucleic acid probes or primers described herein. In another approach, alternate splice variants can be predicted using various methods, computer programs, or computer systems available to practitioners in the field.  
     [0101] General methods for splice site prediction can be found in Nakata, 1985,  Nucleic Acids Res.  13:5327-5340. In addition, splice sites can be predicted using, for example, the GRAIL™ (E. C. Uberbacher and R. J. Mural, 1991,  Proc. Natl. Acad. Sci. USA,  88:11261-11265; E. C. Uberbacher, 1995,  Trends Biotech.,  13:497-500; http://grail.lsd.ornl.gov/grailexp); GenView (L. Milanesi et al., 1993,  Proceedings of the Second International Conference on Bioinformatics, Supercomputing, and Complex Genome Analysis,  H. A. Lim et al. (eds), World Scientific Publishing, Singapore, pp. 573-588; http://l25.itba.mi.cnr.it/˜webgene/wwwgene_help.html); SpliceView (http://www.itba.mi.cnr.it/webgene); and HSPL (V. V. Solovyev et al., 1994,  Nucleic Acids Res.  22:5156-5163; V. V. Solovyev et al., 1994, “The Prediction of Human Exons by Oligonucleotide Composition and Discriminant Analysis of Spliceable Open Reading Frames,” R. Altman et al. (eds),  The Second International conference on Intelligent systems for Molecular Biology,  AAAI Press, Menlo Park, Calif., pp. 354-362; V. V. Solovyev et al., 1993, “Identification Of Human Gene Functional Regions Based On Oligonucleotide Composition,” L. Hunter et al. (eds),  In Proceedings of First International conference on Intelligent System for Molecular Biology,  Bethesda, pp. 371-379) computer systems.  
     [0102] Additionally, computer programs such as GeneParser (E. E. Snyder and G. D. Stormo, 1995,  J. Mol. Biol.  248: 1-18; E. E. Snyder and G. D. Stormo, 1993,  Nucl. Acids Res.  21(3): 607-613; http://mcdb.colorado.edu/˜eesnyder/GeneParser.html); MZEF (M. Q. Zhang, 1997,  Proc. Natl. Acad. Sci. USA,  94:565-568; http://argon.cshl.org/genefinder); MORGAN (S. Salzberg et al., 1998,  J. Comp. Biol.  5:667-680; S. Salzberg et al. (eds), 1998,  Computational Methods in Molecular Biology,  Elsevier Science, New York, N.Y., pp. 187-203); VEIL (J. Henderson et al., 1997,  J. Comp. Biol.  4:127-141); GeneScan (S. Tiwari et al., 1997,  CABIOS  ( BioInformatics ) 13: 263-270); GeneBuilder (L. Milanesi et al., 1999,  Bioinformatics  15:612-621); Eukaryotic GeneMark (J. Besemer et al., 1999,  Nucl. Acids Res.  27:3911-3920); and FEXH (V. V. Solovyev et al., 1994,  Nucleic Acids Res.  22:5156-5163). In addition, splice sites (i.e., former or potential splice sites) in cDNA sequences can be predicted using, for example, the RNASPL (V. V. Solovyev et al., 1994,  Nucleic Acids Res.  22:5156-5163); or INTRON (A. Globek et al., 1991, INTRON version 1.1 manual, Laboratory of Biochemical Genetics, NIMH, Washington, D.C.) programs.  
     [0103] The present invention also encompasses naturally-occurring polymorphisms of ADAM or Interactor genes. As will be understood by those in the art, the genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution generating variant forms of gene sequences (Gusella, 1986,  Ann. Rev. Biochem.  55:831-854). Restriction fragment length polymorphisms (RFLPs) include variations in DNA sequences that alter the length of a restriction fragment in the sequence (Botstein et al., 1980,  Am. J. Hum. Genet.  32, 314-331). RFLPs have been widely used in human and animal genetic analyses (see WO 90/13668; WO90/11369; Donis-Keller, 1987,  Cell  51:319-337; Lander et al., 1989,  Genetics  121: 85-99). Short tandem repeats (STRs) include tandem di-, tri- and tetranucleotide repeated motifs, also termed variable number tandem repeat (VNTR) polymorphisms. VNTRs have been used in identity and paternity analysis (U.S. Pat. No. 5,075,217; Armour et al., 1992,  FEBS Lett.  307:113-115; Horn et al., WO 91/14003; Jeffreys, EP 370,719), and in a large number of genetic mapping studies.  
     [0104] Single nucleotide polymorphisms (SNPs) are far more frequent than RFLPS, STRs, and VNTRs. SNPs may occur in protein coding (e.g., exon), or non-coding (e.g., intron, 5′UTR, 3′UTR) sequences. SNPs in protein coding regions may comprise silent mutations that do not alter the amino acid sequence of a protein. Alternatively, SNPs in protein coding regions may produce conservative or non-conservative amino acid changes, described in detail below. In some cases, SNPs, including SNP alleles and haplotypes, may give rise to the expression of a defective or other variant protein and, potentially, a genetic disease. SNPs within protein-coding sequences can give rise to genetic diseases, for example, in the β-globin (sickle cell anemia) and CFTR (cystic fibrosis) genes. In non-coding sequences, SNPs may also result in defective protein expression (e.g., as a result of defective splicing). Other single nucleotide polymorphisms have no phenotypic effects.  
     [0105] Single nucleotide polymorphisms can be used in the same manner as RFLPs and VNTRs, but offer several advantages. Single nucleotide polymorphisms tend to occur with greater frequency and are typically spaced more uniformly throughout the genome than other polymorphisms. Also, different SNPs are often easier to distinguish than other types of polymorphisms (e.g., by use of assays employing allele-specific hybridization probes or primers). In one embodiment of the present invention, an ADAM or Interactor nucleic acid contains at least one SNP as set forth in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , described herein. Various combinations, alleles and haplotypes of these SNPs are also encompassed by the invention. In a preferred aspect, an ADAM or Interactor SNP allele or haplotype is associated with a lung-related disorder, such as asthma. Nucleic acids comprising such SNP alleles and haplotypes can be used as diagnostic or therapeutic reagents.  
     [0106] The nucleic acid sequences of the present invention may be derived from a variety of sources including DNA, cDNA, synthetic DNA, synthetic RNA, or combinations thereof. Such sequences may comprise genomic DNA, which may or may not include naturally occurring introns. Moreover, such genomic DNA may be obtained in association with promoter regions or poly(A)+ sequences. The sequences, genomic DNA, or cDNA may be obtained in any of several ways. Genomic DNA can be extracted and purified from suitable cells by means well known in the art. Alternatively, mRNA can be isolated from a cell and used to produce cDNA by reverse transcription or other means.  
     [0107] The nucleic acids described herein are used in the methods of the present invention for production of proteins or polypeptides, through incorporation into cells, tissues, or organisms. In one embodiment, DNA containing all or part of the coding sequence for an ADAM or Interactor polypeptide, or DNA which hybridizes to DNA having the sequence of any one of the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , or a fragment thereof, is incorporated into a vector for expression of the encoded polypeptide in suitable host cells. The encoded amino acid sequence consisting of an ADAM or Interactor polypeptide, or its functional equivalent is capable of normal activity, such as antigenic or intracellular activity.  
     [0108] The invention also concerns the use of the nucleotide sequence of the nucleic acids of this invention to identify DNA probes for ADAM or Interactor genes, PCR primers to amplify ADAM or Interactor genes, nucleotide polymorphisms in ADAM or Interactor genes, and regulatory elements of ADAM or Interactor genes.  
     [0109] The nucleic acids of the present invention find use as primers and templates for the recombinant production of disorder-associated peptides or polypeptides, for chromosome and gene mapping, to provide antisense sequences, for tissue distribution studies, to locate and obtain full length genes, to identify and obtain homologous sequences (wild-type and mutants), and in diagnostic applications. The primers of this invention may comprise all or a portion of the nucleotide sequence of any one shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , or a complementary sequence thereof.  
     [0110] Probes may also be used for the detection of ADAM or Interactor-related sequences, and should preferably contain at least 50%, preferably at least 80%, identity to an ADAM or Interactor polynucleotide, or a complementary sequence, or fragments thereof. The probes of this invention may be DNA or RNA, the probes may comprise all or a portion of the nucleotide sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , or a complementary sequence thereof, and may include promoter, enhancer elements, and introns of the naturally occurring ADAM or Interactor polynucleotide.  
     [0111] The probes and primers based on the ADAM and Interactor gene sequences disclosed herein are used to identify homologous ADAM and Interactor gene sequences and proteins in other species. These ADAM and Interactor gene sequences and proteins are used in the diagnostic/prognostic, therapeutic and drug-screening methods described herein for the species from which they have been isolated.  
     VECTORS AND HOST CELLS  
     [0112] The nucleic acids described herein are used in the methods of the present invention for production of proteins or polypeptides, through incorporation into cells, tissues, or organisms. In one embodiment, DNA containing all or part of the coding sequence for an ADAM or Interactor polypeptide, or DNA which hybridizes to DNA having the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , is incorporated into a vector for expression of the encoded polypeptide in suitable host cells. The encoded polypeptides consisting of ADAM or Interactor genes, or their functional equivalents and are capable of normal activity. A large number of vectors, including bacterial, yeast, and mammalian vectors, have been described for replication and expression in various host cells or cell-free systems, and may be used for gene therapy as well as for simple cloning or protein expression.  
     [0113] In one aspect, an expression vectors comprises a nucleic acid encoding an ADAM or Interactor polypeptide or peptide, as described herein, operably linked to at least one regulatory sequence. Regulatory sequences are known in the art and are selected to direct expression of the desired protein in an appropriate host cell. Accordingly, the term regulatory sequence includes promoters, enhancers and other expression control elements (see D. V. Goeddel, 1990,  Methods Enzymol.  185:3-7). Enhancer and other expression control sequences are described in  Enhancers and Eukaryotic Gene Expression,  1983, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. It should be understood that the design of the expression vector may depend on such factors as the choice of the host cell to be transfected or the type of polypeptide to be expressed.  
     [0114] Several regulatory elements (e.g., promoters) have been isolated and shown to be effective in the transcription and translation of heterologous proteins in the various hosts. Such regulatory regions, methods of isolation, manner of manipulation, etc. are known in the art. Non-limiting examples of bacterial promoters include the β-lactamase (penicillinase) promoter; lactose promoter; tryptophan (trp) promoter; araBAD (arabinose) operon promoter; lambda-derived P 1  promoter and N gene ribosome binding site; and the hybrid tac promoter derived from sequences of the trp and lac UV5 promoters. Non-limiting examples of yeast promoters include the 3-phosphoglycerate kinase promoter, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoter, galactokinase (GAL1) promoter, galactoepimerase promoter, and alcohol dehydrogenase (ADH1) promoter. Suitable promoters for mammalian cells include, without limitation, viral promoters, such as those from Simian Virus 40 (SV40), Rous sarcoma virus (RSV), adenovirus (ADV), and bovine papilloma virus (BPV). Preferred replication and inheritance systems include M13, ColE1, SV40, baculovirus, lambda, adenovirus, CEN ARS, 2 μm ARS and the like. While expression vectors may replicate autonomously, they may also replicate by being inserted into the genome of the host cell, by methods well known in the art.  
     [0115] To obtain expression in eukaryotic cells, terminator sequences, polyadenylation sequences, and enhancer sequences that modulate gene expression may be required. Sequences that cause amplification of the gene may also be desirable. These sequences are well known in the art. Furthermore, sequences that facilitate secretion of the recombinant product from cells, including, but not limited to, bacteria, yeast, and animal cells, such as secretory signal sequences or preprotein or proprotein sequences, may also be included. Such sequences are well described in the art.  
     [0116] Expression and cloning vectors will likely contain a selectable marker, a gene encoding a protein necessary for survival or growth of a host cell transformed with the vector. The presence of this gene ensures growth of only those host cells that express the inserts. Typical selection genes encode proteins that 1) confer resistance to antibiotics or other toxic substances, e.g., ampicillin, neomycin, methotrexate, etc.; 2) complement auxotrophic deficiencies, or 3) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli. Markers may be an inducible or non-inducible gene and will generally allow for positive selection. Non-limiting examples of markers include the ampicillin resistance marker (i.e., beta-lactamase), tetracycline resistance marker, neomycin/kanamycin resistance marker (i.e., neomycin phosphotransferase), dihydrofolate reductase, glutamine synthetase, and the like. The choice of the proper selectable marker will depend on the host cell, and appropriate markers for different hosts as understood by those of skill in the art.  
     [0117] Suitable expression vectors for use with the present invention include, but are not limited to, pUC, pBluescript (Stratagene), pET (Novagen, Inc., Madison, Wis.), and pREP (Invitrogen) plasmids. Vectors can contain one or more replication and inheritance systems for cloning or expression, one or more markers for selection in the host, e.g., antibiotic resistance, and one or more expression cassettes. The inserted coding sequences can be synthesized by standard methods, isolated from natural sources, or prepared as hybrids. Ligation of the coding sequences to transcriptional regulatory elements (e.g., promoters, enhancers, and insulators) or to other amino acid encoding sequences can be carried out using established methods.  
     [0118] Suitable cell-free expression systems for use with the present invention include, without limitation, rabbit reticulocyte lysate, wheat germ extract, canine pancreatic microsomal membranes,  E. coli  S30 extract, and coupled transcription/translation systems (Promega Corp., Madison, Wis.). These systems allow the expression of recombinant polypeptides or peptides upon the addition of cloning vectors, DNA fragments, or RNA sequences containing protein-coding regions and appropriate promoter elements.  
     [0119] Non-limiting examples of suitable host cells include bacteria, archea, insect, fungi (e.g., yeast), plant, and animal cells (e.g., mammalian, especially human). Of particular interest are  Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae,  SF9 cells, C129 cells, 293 cells, Neurospora, and immortalized mammalian myeloid and lymphoid cell lines. Techniques for the propagation of mammalian cells in culture are well-known (see, Jakoby and Pastan (eds), 1979,  Cell Culture. Methods in Enzymology,  volume 58, Academic Press, Inc., Harcourt Brace Jovanovich, N.Y.). Examples of commonly used mammalian host cell lines are VERO and HeLa cells, CHO cells, and WI38, BHK, and COS cell lines, although it will be appreciated by the skilled practitioner that other cell lines may be used, e.g., to provide higher expression desirable glycosylation patterns, or other features.  
     [0120] Host cells can be transformed, transfected, or infected as appropriate by any suitable method including electroporation, calcium chloride-, lithium chloride-, lithium acetate/polyethylene glycol-, calcium phosphate-, DEAE-dextran-, liposome-mediated DNA uptake, spheroplasting, injection, microinjection, microprojectile bombardment, phage infection, viral infection, or other established methods. Alternatively, vectors containing the nucleic acids of interest can be transcribed in vitro, and the resulting RNA introduced into the host cell by well-known methods, e.g., by injection (see, Kubo et al., 1988,  FEBS Letts.  241:119). The cells into which have been introduced nucleic acids described above are meant to also include the progeny of such cells.  
     [0121] The nucleic acids of the invention may be isolated directly from cells. Alternatively, the polymerase chain reaction (PCR) method can be used to produce the nucleic acids of the invention, using either RNA (e.g., mRNA) or DNA (e.g., genomic DNA) as templates. Primers used for PCR can be synthesized using the sequence information provided herein and can further be designed to introduce appropriate new restriction sites, if desirable, to facilitate incorporation into a given vector for recombinant expression.  
     [0122] Using the information provided in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , one skilled in the art will be able to clone and sequence all representative nucleic acids of interest, including nucleic acids encoding complete protein-coding sequences. It is to be understood that non-protein-coding sequences contained within the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12  are also within the scope of the invention. Such sequences include, without limitation, sequences important for replication, recombination, transcription, and translation. Non-limiting examples include promoters and regulatory binding sites involved in regulation of gene expression, and 5′- and 3′-untranslated sequences (e.g., ribosome-binding sites) that form part of mRNA molecules.  
     [0123] The nucleic acids of this invention can be produced in large quantities by replication in a suitable host cell. Natural or synthetic nucleic acid fragments, comprising at least ten contiguous bases coding for a desired peptide or polypeptide can be incorporated into recombinant nucleic acid constructs, usually DNA constructs, capable of introduction into and replication in a prokaryotic or eukaryotic cell. Usually the nucleic acid constructs will be suitable for replication in a unicellular host, such as yeast or bacteria, but may also be intended for introduction to (with and without integration within the genome) cultured mammalian or plant or other eukaryotic cells, cell lines, tissues, or organisms. The purification of nucleic acids produced by the methods of the present invention is described, for example, in Sambrook et al., 1989; F. M. Ausubel et al., 1992,  Current Protocols in Molecular Biology,  J. Wiley and Sons, New York, N.Y.  
     [0124] The nucleic acids of the present invention can also be produced by chemical synthesis, e.g., by the phosphoramidite method described by Beaucage et al., 1981,  Tetra. Letts.  22:1859-1862, or the triester method according to Matteucci et al., 1981,  J. Am. Chem. Soc.,  103:3185, and can performed on commercial, automated oligonucleotide synthesizers. A double-stranded fragment may be obtained from the single-stranded product of chemical synthesis either by synthesizing the complementary strand and annealing the strands together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence.  
     [0125] These nucleic acids can encode full-length variant forms of proteins as well as the wild-type protein. The variant proteins (which could be especially useful for detection and treatment of disorders) will have the variant amino acid sequences encoded by the polymorphisms described in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12  when said polymorphisms are read so as to be in-frame with the full-length coding sequence of which it is a component.  
     [0126] Large quantities of the nucleic acids and proteins of the present invention may be prepared by expressing the ADAM or Interactor gene nucleic acids or portions thereof in vectors or other expression vectors in compatible prokaryotic or eukaryotic host cells. The most commonly used prokaryotic hosts are strains of  Escherichia coli,  although other prokaryotes, such as  Bacillus subtilis  or Pseudomonas may also be used. Mammalian or other eukaryotic host cells, such as those of yeast, filamentous fungi, plant, insect, or amphibian or avian species, may also be useful for production of the proteins of the present invention. For example, insect cell systems (i.e., lepidopteran host cells and baculovirus expression vectors) are particularly suited for large-scale protein production.  
     [0127] Host cells carrying an expression vector (i.e., transformants or clones) are selected using markers depending on the mode of the vector construction. The marker may be on the same or a different DNA molecule, preferably the same DNA molecule. In prokaryotic hosts, the transformant may be selected, e.g., by resistance to ampicillin, tetracycline or other antibiotics. Production of a particular product based on temperature sensitivity may also serve as an appropriate marker.  
     [0128] Prokaryotic or eukaryotic cells comprising the nucleic acids of the present invention will be useful not only for the production of the nucleic acids and proteins of the present invention, but also, for example, in studying the characteristics of ADAM or Interactor proteins and protein variants. Cells and animals that carry an ADAM or Interactor gene can be used as model systems to study and test for substances that have potential as therapeutic agents. The cells are typically cultured mesenchymal stem cells. These may be isolated from individuals with a somatic or germine ADAM or Interactor gene. Alternatively, the cell line can be engineered to carry an ADAM or Interactor gene, as described above. After a test substance is applied to the cells, the transformed phenotype of the cell is determined. Any trait of transformed cells can be assessed, including respiratory diseases including asthma, atopy, and response to application of putative therapeutic agents.  
     ANTISENSE NUCLEIC ACIDS  
     [0129] A further embodiment of the invention is antisense nucleic acids or oligonucleotides which are complementary, in whole or in part, to a target molecule comprising a sense strand, and can hybridize with the target molecule. The target can be DNA, or its RNA counterpart (i.e., wherein T residues of the DNA are U residues in the RNA counterpart). When introduced into a cell, antisense nucleic acids or oligonucleotides can inhibit the expression of the gene encoded by the sense strand or the mRNA transcribed from the sense strand. Antisense nucleic acids can be produced by standard techniques. See, for example, Shewmaker, et al., U.S. Pat. No. 5,107,065.  
     [0130] In a particular embodiment, an antisense nucleic acid or oligonucleotide is wholly or partially complementary to and can hybridize with a target nucleic acid (either DNA or RNA), wherein the target nucleic acid can hybridize to a nucleic acid having the sequence of the complement of the strands shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 . For example, an antisense nucleic acid or oligonucleotide can be complementary to a target nucleic acid having the sequence shown as the strand of the open reading frames in column 4 of Table 2, or nucleic acids encoding functional equivalents of ADAM or Interactor genes, or to a portion of these nucleic acids sufficient to allow hybridization. A portion, for example a sequence of 16 nucleotides, could be sufficient to inhibit expression of the protein. Or, an antisense nucleic acid or oligonucleotide, complementary to 5′ or 3′ untranslated regions, or overlapping the translation initiation codons (5′ untranslated and translated regions), of ADAM or Interactor genes, or genes encoding a functional equivalent can also be effective. In another embodiment, the antisense nucleic acid is wholly or partially complementary to and can hybridize with a target nucleic acid that encodes an ADAM or Interactor polypeptide.  
     [0131] In addition to the antisense nucleic acids of the invention, oligonucleotides can be constructed which will bind to duplex nucleic acids either in the genes or the DNA:RNA complexes of transcription, to form stable triple helix-containing or triplex nucleic acids to inhibit transcription and expression of a gene encoding an ADAM or Interactor gene, or their functional equivalents (Frank-Kamenetskii, M. D. and Mirkin, S. M., 1995,  Ann. Rev. Biochem.  64:65-95). Such oligonucleotides of the invention are constructed using the base-pairing rules of triple helix formation and the nucleotide sequences of the genes or mRNAs for ADAM or Interactor genes.  
     [0132] In preferred embodiments, at least one of the phosphodiester bonds of an antisense oligonucleotide has been substituted with a structure that functions to enhance the ability of the compositions to penetrate into the region of cells where the RNA whose activity is to be modulated is located. It is preferred that such substitutions comprise phosphorothioate bonds, methyl phosphonate bonds, or short chain alkyl or cycloalkyl structures. In accordance with other preferred embodiments, the phosphodiester bonds are substituted with structures which are, at once, substantially non-ionic and non-chiral, or with structures which are chiral and enantiomerically specific. Persons of ordinary skill in the art will be able to select other linkages for use in the practice of the invention.  
     [0133] Oligonucleotides may also include species that include at least some modified base forms. Thus, purines and pyrimidines other than those normally found in nature may be so employed. Similarly, modifications on the furanosyl portions of the nucleotide subunits may also be effected, as long as the essential tenets of this invention are adhered to. Examples of such modifications are 2′-O-alkyl- and 2′-halogen-substituted nucleotides. Some non-limiting examples of modifications at the 2′ position of sugar moieties which are useful in the present invention include OH, SH, SCH 3 , F, OCH 3 , OCN, O(CH 2 ) n NH 2  and O(CH 2 ) n  CH 3 , where n is from 1 to about 10. Such oligonucleotides are functionally interchangeable with natural oligonucleotides or synthesized oligonucleotides, which have one or more differences from the natural structure. All such analogs are comprehended by this invention so long as they function effectively to hybridize with an ADAM or Interactor nucleic acid to inhibit the function thereof.  
     [0134] The oligonucleotides in accordance with this invention preferably comprise from about 3 to about 50 subunits. It is more preferred that such oligonucleotides and analogs comprise from about 8 to about 25 subunits and still more preferred to have from about 12 to about 20 subunits. As defined herein, a “subunit” is a base and sugar combination suitably bound to adjacent subunits through phosphodiester or other bonds.  
     [0135] Antisense nucleic acids or oligonulcleotides can be produced by standard techniques (see, e.g., Shewmaker et al., U.S. Pat. No. 5,107,065. The oligonucleotides used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is available from several vendors, including PE Applied Biosystems (Foster City, Calif.). Any other means for such synthesis may also be employed, however, the actual synthesis of the oligonucleotides is well within the abilities of the practitioner. It is also well known to prepare other oligonucleotide such as phosphorothioates and alkylated derivatives.  
     [0136] The oligonucleotides of this invention are designed to be hybridizable with ADAM or Interactor RNA (e.g., mRNA) or DNA. For example, an oligonucleotide (e.g., DNA oligonucleotide) that hybridizes to ADAM or Interactor mRNA can be used to target the mRNA for RnaseH digestion. Alternatively, an oligonucleotide that hybridizes to the translation initiation site of ADAM or Interactor mRNA can be used to prevent translation of the mRNA. In another approach, oligonucleotides that bind to the double-stranded DNA of an ADAM or Interactor gene can be administered. Such oligonucleotides can form a triplex construct and inhibit the transcription of the DNA encoding ADAM or Interactor polypeptides. Triple helix pairing prevents the double helix from opening sufficiently to allow the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described (see, e.g., J. E. Gee et al., 1994,  Molecular and Immunologic Approaches,  Futura Publishing Co., Mt. Kisco, N.Y.).  
     [0137] As non-limiting examples, antisense oligonucleotides may be targeted to hybridize to the following regions: mRNA cap region; translation initiation site; translational termination site; transcription initiation site; transcription termination site; polyadenylation signal; 3′ untranslated region; 5′ untranslated region; 5′ coding region; mid coding region; and 3′ coding region. Preferably, the complementary oligonucleotide is designed to hybridize to the most unique 5′ sequence of an ADAM or Interactor gene, including any of about 15-35 nucleotides spanning the 5′ coding sequence. Appropriate oligonucleotides can be designed using OLIGO software (Molecular Biology Insights, Inc., Cascade, Colo.; http://www.oligo.net).  
     [0138] In accordance with the present invention, an antisense oligonucleotide can be synthesized, formulated as a pharmaceutical composition, and administered to a subject. The synthesis and utilization of antisense and triplex oligonucleotides have been previously described (e.g., H. Simon et al., 1999,  Antisense Nucleic Acid Drug Dev.  9:527-31; F. X. Barre et al., 2000,  Proc. Natl. Acad. Sci. USA  97:3084-3088; R. Elez et al., 2000,  Biochem. Biophys. Res. Commun.  269:352-6; E. R. Sauter et al., 2000,  Clin. Cancer Res.  6:654-60). Alternatively, expression vectors derived from retroviruses, adenovirus, herpes or vaccinia viruses, or from various bacterial plasmids may be used for delivery of nucleotide sequences to the targeted organ, tissue or cell population. Methods that are well known to those skilled in the art can be used to construct recombinant vectors that will express nucleic acid sequence that is complementary to the nucleic acid sequence encoding an ADAM or Interactor polypeptide. These techniques are described both in Sambrook et al., 1989 and in Ausubel et al., 1992. For example, ADAM or Interactor gene expression can be inhibited by transforming a cell or tissue with an expression vector that expresses high levels of untranslatable ADAM or Interactor sense or antisense sequences. Even in the absence of integration into the DNA, such vectors may continue to transcribe RNA molecules until they are disabled by endogenous nucleases. Transient expression may last for a month or more with a non-replicating vector, and even longer if appropriate replication elements included in the vector system.  
     [0139] Various assays may be used to test the ability of antisense oligonucleotides to inhibit ADAM or Interactor gene expression. For example, ADAM or Interactor mRNA levels can be assessed Northern blot analysis (Sambrook et al., 1989; Ausubel et al., 1992; J. C. Alwine et al. 1977,  Proc. Natl. Acad. Sci. USA  74:5350-5354; I. M. Bird, 1998,  Methods Mol. Biol.  105:325-36), quantitative or semi-quantitative RT-PCR analysis (see, e.g., W. M. Freeman et al., 1999,  Biotechniques  26:112-122; Ren et al., 1998,  Mol. Brain Res.  59:256-63; J. M. Cale et al., 1998,  Methods Mol. Biol.  105:351-71), or in situ hybridization (reviewed by A. K. Raap, 1998,  Mutat. Res.  400:287-298). Alternatively, ADAM or Interactor polypeptide levels can be measured, e.g., by western blot analysis, indirect immunofluorescence, immunoprecipitation techniques (see, e.g., J. M. Walker, 1998,  Protein Protocols on CD - ROM,  Humana Press, Totowa, N.J.).  
     POLYPEPTIDES  
     [0140] The invention also relates to ADAM or Interactor proteins or polypeptides encoded by the nucleic acids described herein, see Table 2, or portions or variants thereof. The proteins and polypeptides of this invention can be isolated or recombinant. In a preferred embodiment, the proteins or portions thereof have at least one function characteristic of an ADAM or Interactor protein or polypeptide. These proteins are referred to as analogs, and the genes encoding them include, for example, naturally occurring ADAM or Interactor genes, variants (e.g., mutants) encoding those proteins or portions thereof. Such protein or polypeptide variants include mutants differing by the addition, deletion or substitution of one or more amino acid residues, or modified polypeptides in which one or more residues are modified (e.g., by phosphorylation, sulfation, acylation, etc.), and mutants comprising one or more modified residues. The variant can have “conservative” changes, wherein a substituted amino acid has similar structural or chemical properties, e.g., replacement of leucine with isoleucine. More infrequently, a variant can have “nonconservative” changes, e.g., replacement of a glycine with a tryptophan. Guidance in determining which amino acid residues can be substituted, inserted, or deleted without abolishing biological or immunological activity can be determined using computer programs well known in the art, for example, DNASTAR software (DNASTAR, Inc., Madison, Wis.).  
     [0141] As non-limiting examples, conservative substitutions in an ADAM or Interactor amino acid sequence can be made in accordance with the following table:  
                                                           Original   Conservative   Original   Conservative           Residue   Substitution(s)   Residue   Substitution(s)                          Ala   Ser   Leu   Ile, Val           Arg   Lys   Lys   Arg, Gln, Glu           Asn   Gln, His   Met   Leu, Ile           Asp   Glu   Phe   Met, Leu, Tyr           Cys   Ser   Ser   Thr           Gln   Asn   Thr   Ser           Glu   Asp   Trp   Tyr           Gly   Pro   Tyr   Trp, Phe           His   Asn, Gln   Val   Ile, Leu           Ile   Leu, Val                      
 
     [0142] Substantial changes in function or immunogenicity can be made by selecting substitutions that are less conservative than those shown in the table, above. For example, non-conservative substitutions can be made which more significantly affect the structure of the polypeptide in the area of the alteration, for example, the alpha-helical, or beta-sheet structure; the charge or hydrophobicity of the molecule at the target site; or the bulk of the side chain. The substitutions which generally are expected to produce the greatest changes in the polypeptide&#39;s properties are those where 1) a hydrophilic residue, e.g., seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl, or alanyl; 2) a cysteine or proline is substituted for (or by) any other residue; 3) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl; or 4) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) a residue that does not have a side chain, e.g., glycine.  
     [0143] In one embodiment, the percent amino acid sequence identity between an ADAM or Interactor polypeptide such as those shown in Table 2, and functional equivalents thereof is at least 50%. In a preferred embodiment, the percent amino acid sequence identity between such an ADAM or Interactor polypeptide and its functional equivalents is at least 65%. More preferably, the percent amino acid sequence identity of an ADAM or Interactor polypeptide and its functional equivalents is at least 75%, still more preferably, at least 80%, and even more preferably, at least 90%.  
     [0144] Percent sequence identity can be calculated using computer programs or direct sequence comparison. Preferred computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package, FASTA, BLASTP, and TBLASTN (see, e.g., D. W. Mount, 2001,  Bioinformatics: Sequence and Genome Analysis,  Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The well-known Smith Waterman algorithm may also be used to determine identity.  
     [0145] Exemplary parameters for amino acid sequence comparison include the following: 1) algorithm from Needleman and Wunsch, 1970,  J Mol. Biol.  48:443-453; 2) BLOSSUM62 comparison matrix from Hentikoff and Hentikoff, 1992,  Proc. Natl. Acad. Sci. USA  89:10915-10919; 3) gap penalty=12; and 4) gap length penalty=4. A program useful with these parameters is publicly available as the “gap” program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are the default parameters for polypeptide comparisons (with no penalty for end gaps).  
     [0146] Alternatively, polypeptide sequence identity can be calculated using the following equation: % identity=(the number of identical residues)/(alignment length in amino acid residues)*100. For this calculation, alignment length includes internal gaps but does not include terminal gaps.  
     [0147] In accordance with the present invention, polypeptide sequences may be identical to the sequence of any one of the sequences shown in Table 2, or may include up to a certain integer number of amino acid alterations. Polypeptide alterations are selected from the group consisting of at least one amino acid deletion, substitution, including conservative and non-conservative substitution, or insertion. Alterations may occur at the amino- or carboxy-terminal positions of the reference polypeptide sequence or anywhere between those terminal positions, interspersed either individually among the amino acids in the reference sequence or in one or more contiguous groups within the reference sequence.  
     [0148] In specific embodiments, a polypeptide variant may be encoded by an ADAM or Interactor nucleic acid comprising a SNP, allele, haplotype, or an alternate splice variant. For example, a polypeptide variant may be encoded by an ADAM or Interactor gene variant comprising a nucleotide sequence of any one of sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 .  
     [0149] The invention also relates to isolated, synthesized or recombinant portions or fragments of ADAM or Interactor protein or polypeptide as described herein. Polypeptide fragments (i.e., peptides) can be made which have full or partial function on their own, or which when mixed together (though fully, partially, or nonfunctional alone), spontaneously assemble with one or more other polypeptides to reconstitute a functional protein having at least one functional characteristic of an ADAM or Interactor protein of this invention. In addition, ADAM or Interactor polypeptide fragments may comprise, for example, one or more domains of the ADAM or Interactor polypeptide, disclosed herein.  
     [0150] Polypeptides according to the invention can comprise at least 5 contiguous amino acid residues; preferably the polypeptides comprise at least 12 contiguous residues; more preferably the polypeptides comprise at least 20 contiguous residues; and yet more preferably the polypeptides comprise at least 30 contiguous residues. Nucleic acids comprising protein-coding sequences can be used to direct the expression of asthma-associated polypeptides in intact cells or in cell-free translation systems. The coding sequence can be tailored, if desired, for more efficient expression in a given host organism, and can be used to synthesize oligonucleotides encoding the desired amino acid sequences. The resulting oligonucleotides can be inserted into an appropriate vector and expressed in a compatible host organism or translation system.  
     [0151] The polypeptides of the present invention, including function-conservative variants, may be isolated from wild-type or mutant cells (e.g., human cells or cell lines), from heterologous organisms or cells (e.g., bacteria, yeast, insect, plant, and mammalian cells), or from cell-free translation systems (e.g., wheat germ, microsomal membrane, or bacterial extracts) in which a protein-coding sequence has been introduced and expressed. Furthermore, the polypeptides may be part of recombinant fusion proteins. The polypeptides can also, advantageously, be made by synthetic chemistry. Polypeptides may be chemically synthesized by commercially available automated procedures, including, without limitation, exclusive solid phase synthesis, partial solid phase methods, fragment condensation or classical solution synthesis.  
     [0152] Methods for polypeptide purification are well-known in the art, including, without limitation, preparative disc-gel electrophoresis, isoelectric focusing, HPLC, reversed-phase HPLC, gel filtration, ion exchange and partition chromatography, and countercurrent distribution. For some purposes, it is preferable to produce the polypeptide in a recombinant system in which the protein contains an additional sequence (e.g., epitope or protein) tag that facilitates purification. Non-limiting examples of epitope tags include c-myc, haemagglutinin (HA), polyhistidine (6X-HIS) (SEQ ID NO:), GLU-GLU, and DYKDDDDK (SEQ ID NO:) (FLAG®) epitope tags. Non-limiting examples of protein tags include glutathione-S-transferase (GST), green fluorescent protein (GFP), and maltose binding protein (MBP).  
     [0153] In one approach, the coding sequence of a polypeptide or peptide can be cloned into a vector that creates a fusion with a sequence tag of interest. Suitable vectors include, without limitation, pRSET (Invitrogen Corp., San Diego, Calif.), PGEX (Amersham-Pharmacia Biotech, Inc., Piscataway, N.J.), pEGFP (CLONTECH Laboratories, Inc., Palo Alto, Calif.), and PMAL™ (New England BioLabs (NEB), Inc., Beverly, Mass.) plasmids. Following expression, the epitope, or protein tagged polypeptide or peptide can be purified from a crude lysate of the translation system or host cell by chromatography on an appropriate solid-phase matrix. In some cases, it may be preferable to remove the epitope or protein tag (i.e., via protease cleavage) following purification. As an alternative approach, antibodies produced against a disorder-associated protein or against peptides derived therefrom can be used as purification reagents. Other purification methods are also possible.  
     [0154] The present invention also encompasses modifications of an ADAM or Interactor polypeptides. The isolated polypeptides may be modified by, for example, phosphorylation, sulfation, acylation, or other protein modifications. They may also be modified with a label capable of providing a detectable signal, either directly or indirectly, including, but not limited to, radioisotopes and fluorescent compounds, as described in detail herein.  
     [0155] Both the naturally occurring and recombinant forms of the polypeptides of the invention can advantageously be used to screen compounds for binding activity. Many methods of screening for binding activity are known by those skilled in the art and may be used to practice the invention. Several methods of automated assays have been developed in recent years so as to permit screening of tens of thousands of compounds in a short period of time. Such high-throughput screening methods are particularly preferred. The use of high-throughput screening assays to test for inhibitors is greatly facilitated by the availability of large amounts of purified polypeptides, as provided by the invention. The polypeptides of the invention also find use as therapeutic agents as well as antigenic components to prepare antibodies.  
     [0156] The polypeptides of this invention find use as immunogenic components useful as antigens for preparing antibodies by standard methods. It is well known in the art that immunogenic epitopes generally contain at least 5 contiguous amino acid residues (Ohno et al., 1985,  Proc. Natl. Acad. Sci. USA  82:2945). Therefore, the immunogenic components of this invention will typically comprise at least 5 contiguous amino acid residues of the sequence of the complete polypeptide chains. Preferably, they will contain at least 7, and most preferably at least 10 contiguous amino acid residues or more to ensure that they will be immunogenic. Whether a given component is immunogenic can readily be determined by routine experimentation. Such immunogenic components can be produced by proteolytic cleavage of larger polypeptides or by chemical synthesis or recombinant technology and are thus not limited by proteolytic cleavage sites. The present invention thus encompasses antibodies that specifically recognize asthma-associated immunogenic components.  
     STRUCTURAL STUDIES  
     [0157] A purified ADAM or Interactor polypeptide, or portions or complexes thereof, can be analyzed by well-established methods (e.g., X-ray crystallography, NMR, CD, etc.) to determine the three-dimensional structure of the molecule. The three-dimensional structure, in turn, can be used to model intermolecular interactions. Exemplary methods for crystallization and X-ray crystallography are found in P. G. Jones, 1981,  Chemistry in Britain,  17:222-225; C. Jones et al. (eds),  Crystallographic Methods and Protocols,  Humana Press, Totowa, N.J.; A. McPherson, 1982,  Preparation and Analysis of Protein Crystals,  John Wiley &amp; Sons, New York, N.Y.; T. L. Blundell and L. N. Johnson, 1976,  Protein Crystallography,  Academic Press, Inc., New York, N.Y.; A. Holden and P. Singer, 1960,  Crystals and Crystal Growing,  Anchor Books-Doubleday, New York, N.Y.; R. A. Laudise, 1970,  The Growth of Single Crystals,  Solid State Physical Electronics Series, N. Holonyak, Jr., (ed), Prentice-Hall, Inc.; G. H. Stout and L. H. Jensen, 1989,  X - ray Structure Determination: A Practical Guide,  2nd edition, John Wiliey &amp; Sons, New York, N.Y.;  Fundamentals of Analytical Chemistry,  3rd. edition, Saunders Golden Sunburst Series, Holt, Rinehart and Winston, Philadelphia, Pa., 1976; P. D. Boyle of the Department of Chemistry of North Carolina State University at http://laue.chem.ncsu.edu/web/GrowXtal.html; M. B. Berry, 1995,  Protein Crystalization: Theory and Practice, Structure and Dynamics of E. coli Adenylate Kinase,  Doctoral Thesis, Rice University, Houston Tex.; www.bioc.rice.edu/˜berry/papers/crystalization/crystalization.html.  
     [0158] For X-ray diffraction studies, single crystals can be grown to suitable size. Preferably, a crystal has a size of 0.2 to 0.4 mm in at least two of the three dimensions. Crystals can be formed in a solution comprising an ADAM or Interactor polypeptide (e.g., 1.5-200 mg/ml) and reagents that reduce the solubility to conditions close to spontaneous precipitation. Factors that affect the formation of polypeptide crystals include: 1) purity; 2) substrates or co-factors; 3) pH; 4) temperature; 5) polypeptide concentration; and 6) characteristics of the precipitant. Preferably, the ADAM or Interactor polypeptides are pure, i.e., free from contaminating components (at least 95% pure), and free from denatured ADAM or Interactor polypeptides. In particular, polypeptides can be purified by FPLC and HPLC techniques to assure homogeneity (see, Lin et al., 1992,  J. Crystal. Growth.  122:242-245). Optionally, ADAM or Interactor polypeptide substrates or co-factors can be added to stabilize the quaternary structure of the protein and promote lattice packing.  
     [0159] Suitable precipitants for crystallization include, but are not limited to, salts (e.g., ammonium sulphate, potassium phosphate); polymers (e.g., polyethylene glycol (PEG) 6000); alcohols (e.g., ethanol); polyalcohols (e.g., 1-methyl-2,4 pentane diol (MPD)); organic solvents; sulfonic dyes; and deionized water. The ability of a salt to precipitate polypeptides can be generally described by the Hofmeister series: PO 4   3− &gt;HPO 4   2− =SO 4   2− &gt;citrate&gt;CH 3 CO 2   − &gt;Cl − &gt;Br − &gt;NO 3   − &gt;ClO 4   − &gt;SCN − ; and NH 4   + &gt;K + &gt;Na + &gt;Li + . Non-limiting examples of salt precipitants are shown below (see Berry, 1995).  
                                                   Precipitant   Maximum concentration                          (NH 4   + /Na + /Li + ) 2   or   4.0/1.5/2.1/2.5 M           Mg 2  + SO 4   2−             NH 4   + /Na + /K +  PO 4   3−     3.0/4.0/4.0 M           NH 4   + /K + /Na +  Li +  citrate   ˜1.8 M           NH 4   + /K + /Na + /Li +     ˜3.0 M           acetate           NH 4   + /K + /Na + /Li +  Cl −     5.2/9.8/4.2/5.4 M           NH 4   + NO 3   −     ˜8.0 M                      
 
     [0160] High molecular weight polymers useful as precipitating agents include polyethylene glycol (PEG), dextran, polyvinyl alcohol, and polyvinyl pyrrolidone (A. Polson et al., 1964,  Biochem. Biophys. Acta.  82:463-475). In general, polyethylene glycol (PEG) is the most effective for forming crystals. PEG compounds with molecular weights less than 1000 can be used at concentrations above 40% v/v. PEGs with molecular weights above 1000 can be used at concentration 5-50% w/v. Typically, PEG solutions are mixed with ˜0.1% sodium azide to prevent bacterial growth.  
     [0161] Typically, crystallization requires the addition of buffers and a specific salt content to maintain the proper pH and ionic strength for a protein&#39;s stability. Suitable additives include, but are not limited to sodium chloride (e.g., 50-500 mM as additive to PEG and MPD; 0.15-2 M as additive to PEG); potassium chloride (e.g., 0.05-2 M); lithium chloride (e.g., 0.05-2 M); sodium fluoride (e.g., 20-300 mM); ammonium sulfate (e.g., 20-300 mM); lithium sulfate (e.g., 0.05-2 M); sodium or ammonium thiocyanate (e.g., 50-500 mM); MPD (e.g., 0.5-50%); 1,6 hexane diol (e.g., 0.5-10%); 1,2,3 heptane triol (e.g., 0.5-15%); and benzamidine (e.g., 0.5-15%).  
     [0162] Detergents may be used to maintain protein solubility and prevent aggregation. Suitable detergents include, but are not limited to non-ionic detergents such as sugar derivatives, oligoethyleneglycol derivatives, dimethylamine-N-oxides, cholate derivatives, N-octyl hydroxyalkylsulphoxides, sulphobetains, and lipid-like detergents. Sugar-derived detergents include alkyl glucopyranosides (e.g., C8-GP, C9-GP), alkyl thio-glucopyranosides (e.g., C8-tGP), alkyl maltopyranosides (e.g., C10-M, C12-M; CYMAL-3, CYMAL-5, CYMAL-6), alkyl thio-maltopyranosides, alkyl galactopyranosides, alkyl sucroses (e.g., N-octanoylsucrose), and glucamides (e.g., HECAMEG, C-HEGA-10; MEGA-8). Oligoethyleneglycol-derived detergents include alkyl polyoxyethylenes (e.g., C8-E5, C8-En; C12-E8; C12-E9) and phenyl polyoxyethylenes (e.g., Triton X-100). Dimethylamine-N-oxide detergents include, e.g., C10-DAO; DDAO; LDAO. Cholate-derived detergents include, e.g., Deoxy-Big CHAP, digitonin. Lipid-like detergents include phosphocholine compounds. Suitable detergents further include zwitter-ionic detergents (e.g., ZWITTERGENT 3-10; ZWITTERGENT 3-12); and ionic detergents (e.g., SDS).  
     [0163] Crystallization of macromolecules has been performed at temperatures ranging from 60° C. to less than 0° C. However, most molecules can be crystallized at 4° C. or 22° C. Lower temperatures promote stabilization of polypeptides and inhibit bacterial growth. In general, polypeptides are more soluble in salt solutions at lower temperatures (e.g., 4° C.), but less soluble in PEG and MPD solutions at lower temperatures. To allow crystallization at 4° C. or 22° C., the precipitant or protein concentration can be increased or decreased as required. Heating, melting, and cooling of crystals or aggregates can be used to enlarge crystals. In addition, crystallization at both 4° C. and 22° C. can be assessed (A. McPherson, 1992,  J. Cryst. Growth.  122:161-167; C. W. Carter, Jr. and C. W. Carter, 1979,  J. Biol Chem.  254:12219-12223; T. Bergfors, 1993,  Crystalization Lab Manual ).  
     [0164] A crystallization protocol can be adapted to a particular polypeptide or peptide. In particular, the physical and chemical properties of the polypeptide can be considered (e.g., aggregation, stability, adherence to membranes or tubing, internal disulfide linkages, surface cysteines, chelating ions, etc.). For initial experiments, the standard set of crystalization reagents can be used (Hampton Research, Laguna Niguel, Calif.). In addition, the CRYSTOOL program can provide guidance in determining optimal crystallization conditions (Brent Segelke, 1995, Efficiency analysis of sampling protocols used in protein crystallization screening and crystal structure from two novel crystal forms of PLA2, Ph.D. Thesis, University of California, San Diego; http://www.ccp14.ac.uk/ccp/web-mirrors/llnlrupp/crystool/crystool.htm). Exemplary crystallization conditions are shown below (see Berry, 1995).  
                                                   Concentration                   of Major   Concentration       Major Precipitant   Additive   Precipitant   of Additive                  (NH 4 ) 2 SO 4     PEG 400-2000,   2.0-4.0 M   6%-0.5%           MPD, ethanol,           or methanol       Na citrate   PEG 400-2000,   1.4-1.8 M   6%-0.5%           MPD, ethanol,           or methanol       PEG 1000-20000   (NH 4) 2 SO 4 , NaCl,   40-50%   0.2-0.6 M           or Na formate                  
 
     [0165] Robots can be used for automatic screening and optimization of crystallization conditions. For example, the IMPAX and Oryx systems can be used (Douglas Instruments, Ltd., East Garston, United Kingdom). The CRYSTOOL program (Segelke, supra) can be integrated with the robotics programming. In addition, the Xact program can be used to construct, maintain, and record the results of various crystallization experiments (see, e.g., D. E. Brodersen et al., 1999,  J. Appl. Cryst.  32: 1012-1016; G. R. Andersen and J. Nyborg, 1996,  J. Appl. Cryst.  29:236-240). The Xact program supports multiple users and organizes the results of crystallization experiments into hierarchies. Advantageously, Xact is compatible with both CRYSTOOL and Microsoft® Excel programs.  
     [0166] Four methods are commonly employed to crystallize macromolecules: vapor diffusion, free interface diffusion, batch, and dialysis. The vapor diffusion technique is typically performed by formulating a 1:1 mixture of a solution comprising the polypeptide of interest and a solution containing the precipitant at the final concentration that is to be achieved after vapor equilibration. The drop containing the 1:1 mixture of protein and precipitant is then suspended and sealed over the well solution, which contains the precipitant at the target concentration, as either a hanging or sitting drop. Vapor diffusion can be used to screen a large number of crystallization conditions or when small amounts of polypeptide are available. For screening, drop sizes of 1 to 2 μl can be used. Once preliminary crystallization conditions have been determined, drop sizes such as 10 μl can be used. Notably, results from hanging drops may be improved with agarose gels (see K. Provost and M.-C. Robert, 1991,  J. Cryst. Growth.  110:258-264). Free interface diffusion is performed by layering of a low-density solution onto one of higher density, usually in the form of concentrated protein onto concentrated salt. Since the solute to be crystallized must be concentrated, this method typically requires relatively large amounts of protein. However, the method can be adapted to work with small amounts of protein. In a representative experiment, 2 to 5 μl of sample is pipetted into one end of a 20 μl microcapillary pipet. Next, 2 to 5 μl of precipitant is pipetted into the capillary without introducing an air bubble, and the ends of the pipet are sealed. With sufficient amounts of protein, this method can be used to obtain relatively large crystals (see, e.g., S. M. Althoff et al., 1988,  J. Mol. Biol.  199:665-666).  
     [0167] The batch technique is performed by mixing concentrated polypeptide with concentrated precipitant to produce a final concentration that is supersaturated for the solute macromolecule. Notably, this method can employ relatively large amounts of solution (e.g., milliliter quantities), and can produce large crystals. For that reason, the batch technique is not recommended for screening initial crystallization conditions.  
     [0168] The dialysis technique is performed by diffusing precipitant molecules through a semipermeable membrane to slowly increase the concentration of the solute inside the membrane. Dialysis tubing can be used to dialyze milliliter quantities of sample, whereas dialysis buttons can be used to dialyze microliter quantities (e.g., 7-200 μl). Dialysis buttons may be constructed out of glass, perspex, or Teflon™ (see, e.g., Cambridge Repetition Engineers Ltd., Greens Road, Cambridge CB4 3EQ, UK; Hampton Research). Using this method, the precipitating solution can be varied by moving the entire dialysis button or sack into a different solution. In this way, polypeptides can be “reused” until the correct conditions for crystallization are found (see, e.g., C. W. Carter, Jr. et al., 1988,  J. Cryst. Growth.  90:60-73). However, this method is not recommended for precipitants comprising concentrated PEG solutions.  
     [0169] Various strategies have been designed to screen crystallization conditions, including 1) pl screening; 2) grid screening; 3) factorials; 4) solubility assays; 5) perturbation; and 6) sparse matrices. In accordance with the pl screening method, the pl of a polypeptide is presumed to be its crystallization point. Screening at the pl can be performed by dialysis against low concentrations of buffer (less than 20 mM) at the appropriate pH, or by use of conventional precipitants.  
     [0170] The grid screening method can be performed on two-dimensional matrices. Typically, the precipitant concentration is plotted against pH. The optimal conditions can be determined for each axis, and then combined. At that point, additional factors can be tested (e.g., temperature, additives). This method works best with fast-forming crystals, and can be readily automated (see M. J. Cox and P. C. Weber, 1988,  J. Cryst. Growth.  90:318-324). Grid screens are commercially available for popular precipitants such as ammonium sulphate, PEG 6000, MPD, PEG/LiCl, and NaCl (see, e.g., Hamilton Research).  
     [0171] The incomplete factorial method can be performed by 1) selecting a set of ˜20 conditions; 2) randomly assigning combinations of these conditions; 3) grading the success of the results of each experiment using an objective scale; and 4) statistically evaluating the effects of each of the conditions on crystal formation (see, e.g., C. W. Carter, Jr. et al., 1988,  J. Cryst. Growth.  90:60-73). In particular, conditions such as pH, temperature, precipitating agent, and cations can be tested. Dialysis buttons are preferably used with this method. Typically, optimal conditions/combinations can be determined within 35 tests. Similar approaches, such as “footprinting” conditions, may also be employed (see, e.g., E. A. Stura et al., 1991,  J. Cryst. Growth.  110:1-2).  
     [0172] The perturbation approach can be performed by altering crystallization conditions by introducing a series of additives designed to test the effects of altering the structure of bulk solvent and the solvent dielectric on crystal formation (see, e.g., Whitaker et al., 1995,  Biochem.  34:8221-8226). Additives for increasing the solvent dialectric include, but are not limited to, NaCl, KCl, or LiCl (e.g., 200 mM); Na formate (e.g., 200 mM); Na 2 HPO 4  or K 2 HPO 4  (e.g., 200 mM); urea, triachloroacetate, guanidium HCl, or KSCN (e.g., 20-50 mM). A non-limiting list of additives for decreasing the solvent dialectric include methanol, ethanol, isopropanol, or tert-butanol (e.g., 1-5%); MPD (e.g., 1%); PEG 400, PEG 600, or PEG 1000 (e.g., 1-4%); PEG MME (monomethylether) 550, PEG MME 750, PEG MME 2000 (e.g., 1-4%).  
     [0173] As an alternative to the above-screening methods, the sparse matrix approach can be used (see, e.g., J. Jancarik and S.-H. J. Kim, 1991,  Appl. Cryst.  24:409-411; A. McPherson, 1992,  J. Cryst. Growth.  122:161-167; B. Cudney et al., 1994,  Acta. Cryst.  D50:414-423). Sparse matrix screens are commercially available (see, e.g., Hampton Research; Molecular Dimensions, Inc., Apopka, Fla.; Emerald Biostructures, Inc., Lemont, Ill.). Notably, data from Hampton Research sparse matrix screens can be stored and analyzed using ASPRUN software (Douglas Instruments).  
     [0174] Exemplary conditions for an initial screen are shown below (see Berry, 1995).  
     CRYSTALIZATION CONDITIONS  
     [0175] Tray 1:  
                                                  Ammonium sulfate (wells 7-12)                         PEG 8000 (wells 1-6)       1                                                                     20%   20%   20%   35%   35%   35%   2.0 M   2.0 M   2.0 M   2 5 M   2.5 M   2.5 M       pH 5.0   pH 7 0   pH 8 6   pH 5.0   pH 7.0   pH 8.6   pH 5.0   pH 7.0   pH 8.8   pH 5.0   pH 7.0   pH 8.8                                 MPD (wells 13-16)   +TC,17/32 Na Citrate (wells 17-20)   Na/K Phosphate (wells 21-24)                                                             13   14   15   16   17   18   19   20   21   22   23   24               30%   30%   50%   50%   1.3 M   1.3 M   1.5 M   1.5 M   2.0 M   2.0 M   2.5 M   2.5 M       pH 5.8   pH 7.6   pH 5.8   pH 7.6   pH 5.8   pH 7.5   pH 5.8   pH 7.5   pH 6.0   pH 7.4   pH 6.0   pH 7.4                  
 
     [0176] Tray 2:  
                              PEG 2000 MME/0.2 M Ammon. sulfate (wells 25-30)                                             25   26   27   28   29   30                       25%   25%   25%   40%   40%   40%           pH 5.5   pH 7.0   pH 8.5   pH 5.5   pH 7.0   pH 8.5                                  
 
     [0177] The initial screen can be used with hanging or sitting drops. To conserve the sample, tray 2 can be set up several weeks following tray 1. Wells 31-48 of tray 2 can comprise a random set of solutions. Alternatively, solutions can be formulated using sparse methods. Preferably, test solutions cover a broad range of precipitants, additives, and pH (especially pH 5.0-9.0).  
     [0178] Seeding can be used to trigger nucleation and crystal growth (Stura and Wilson, 1990,  J. Cryst. Growth.  110:270-282; C. Thaller et al., 1981,  J. Mol. Biol.  147:465-469; A. McPherson and P. Schlichta, 1988,  J. Cryst. Growth.  90:47-50). In general, seeding can performed by transferring crystal seeds into a polypeptide solution to allow polypeptide molecules to deposit on the surface of the seeds and produce crystals. Two seeding methods can be used: microseeding and macroseeding. For microseeding, a crystal can be ground into tiny pieces and transferred into the protein solution. Alternatively, seeds can be transferred by adding 1-2 μl of the seed solution directly to the equilibrated protein solution. In another approach, seeds can be transferred by dipping a hair in the seed solution and then streaking the hair across the surface of the drop (streak seeding; see Stura and Wilson, supra). For macroseeding, an intact crystal can be transferred into the protein solution (see, e.g., C. Thaller et al., 1981,  J. Mol. Biol.  147:465-469). Preferably, the surface of the crystal seed is washed to regenerate the growing surface prior to being transferred. Optimally, the protein solution for crystallization is close to saturation and the crystal seed is not completely dissolved upon transfer.  
     ANTIBODIES  
     [0179] Another aspect of the invention pertains to antibodies directed to ADAM or Interactor polypeptides, or portions or variants thereof. The invention provides polyclonal and monoclonal antibodies that bind ADAM or Interactor polypeptides or peptides. The antibodies may be elicited in an animal host (e.g., rabbit, goat, mouse, or other non-human mammal) by immunization with disorder-associated immunogenic components. Antibodies may also be elicited by in vitro immunization (sensitization) of immune cells. The immunogenic components used to elicit the production of antibodies may be isolated from cells or chemically synthesized. The antibodies may also be produced in recombinant systems programmed with appropriate antibody-encoding DNA. Alternatively, the antibodies may be constructed by biochemical reconstitution of purified heavy and light chains. The antibodies include hybrid antibodies, chimeric antibodies, and univalent antibodies. Also included are Fab fragments, including Fab 1  and Fab(ab) 2  fragments of antibodies.  
     [0180] In accordance with the present invention, antibodies are directed to ADAM or Interactor genes (e.g., such as the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ), or variants, or portions thereof. For example, antibodies can be produced to bind to an ADAM or Interactor gene polypeptide encoded by an alternate splice variant comprising the nucleotide sequences shown in FIGS.  1 - 12 . As another example, antibodies can be produced to bind to an ADAM or Interactor polypeptide variant encoded by a nucleic acid containing one or more ADAM or Interactor gene SNPs as set forth in SEQ ID. NOs.: 1-9. Such antibodies can be used as diagnostic or therapeutic reagents.  
     [0181] An isolated ADAM or Interactor gene polypeptide, or variant, or portion thereof, can be used as an immunogen to generate antibodies using standard techniques for polyclonal and monoclonal antibody preparation. A full-length ADAM or Interactor polypeptide can be used or, alternatively, the invention provides antigenic peptide portions of ADAM or Interactor polypeptides for use as immunogens. The antigenic peptide of an ADAM or Interactor comprises at least 5 contiguous amino acid residues of the amino acid sequence shown in any one of column 5 of Table 2, or a variant thereof, and encompasses an epitope of an ADAM or Interactor polypeptide such that an antibody raised against the peptide forms a specific immune complex with an ADAM or Interactor amino acid sequence.  
     [0182] An appropriate immunogenic preparation can contain, for example, recombinantly produced ADAM or Interactor polypeptide or a chemically synthesized ADAM or Interactor polypeptide, or portions thereof. The preparation can further include an adjuvant, such as Freund&#39;s complete or incomplete adjuvant, or similar immunostimulatory agent. A number of adjuvants are known and used by those skilled in the art. Non-limiting examples of suitable adjuvants include incomplete Freund&#39;s adjuvant, mineral gels such as alum, aluminum phosphate, aluminum hydroxide, aluminum silica, and surface-active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol. Further examples of adjuvants include N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine (CGP 11637, referred to as nor-MDP), N-acetylmuramyl-Lalanyl-D-isoglutaminyl-L-alanine-2-(1′-2′-dipalmitoyl-sn-glycero-3 hydroxyphosphoryloxy)-ethylamine (CGP 19835A, referred to as MTP-PE), and RIBI, which contains three components extracted from bacteria, monophosphoryl lipid A, trehalose dimycolate and cell wall skeleton (MPL+TDM+CWS) in a 2% squalene/Tween 80 emulsion. A particularly useful adjuvant comprises 5% (wt/vol) squalene, 2.5% Pluronic L121 polymer and 0.2% polysorbate in phosphate buffered saline (Kwak et al., 1992,  New Eng. J. Med.  327:1209-1215). Preferred adjuvants include complete BCG, Detox, (RIBI, Immunochem Research Inc.), ISCOMS, and aluminum hydroxide adjuvant (Superphos, Biosector). The effectiveness of an adjuvant may be determined by measuring the amount of antibodies directed against the immunogenic peptide.  
     [0183] Polyclonal antibodies to ADAM or Interactor polypeptides can be prepared as described above by immunizing a suitable subject with an ADAM or Interactor gene immunogen. The antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized ADAM or Interactor polypeptide or peptide. If desired, the antibody molecules can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction.  
     [0184] At an appropriate time after immunization, e.g., when the antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique (see Kohler and Milstein, 1975,  Nature  256:495-497; Brown et al., 1981,  J. Immunol.  127:539-46; Brown et al., 1980,  J. Biol. Chem.  255:4980-83; Yeh et al., 1976,  PNAS  76:2927-31; and Yeh et al., 1982,  Int J. Cancer  29:269-75), the human B cell hybridoma technique (Kozbor et al., 1983,  Immunol. Today  4:72), the EBV-hybridoma technique (Cole et al., 1985,  Monoclonal Antibodies and Cancer Therapy,  Alan R. Liss, Inc., pp. 77-96) or trioma techniques.  
     [0185] The technology for producing hybridomas is well-known (see generally R. H. Kenneth, 1980,  Monoclonal Antibodies: A New Dimension In Biological Analyses,  Plenum Publishing Corp., New York, N.Y.; E. A. Lerner, 1981,  Yale J. Biol. Med.,  54:387-402; M. L. Gefter et al., 1977,  Somatic Cell Genet.  3:231-36). In general, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with an ADAM or Interactor immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds ADAM or Interactor polypeptides or peptides.  
     [0186] Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody to an ADAM or Interactor polypeptide (see, e.g., G. Galfre et al., 1977,  Nature  266:55052; Gefter et al., 1977; Lerner, 1981; Kenneth, 1980). Moreover, the ordinarily skilled worker will appreciate that there are many variations of such methods. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. For example, murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the present invention with an immortalized mouse cell line. Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin, and thymidine (HAT medium). Any of a number of myeloma cell lines can be used as a fusion partner according to standard techniques, e.g., the P3-NS1/1-Ag4-1, P3-x63-Ag8.653, or Sp2/O-Ag14 myeloma lines. These myeloma lines are available from ATCC (American Type Culture Collection, Manassas, Va.). Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol (PEG). Hybridoma cells resulting from the fusion arc then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind ADAM or Interactor polypeptides or peptides, e.g., using a standard ELISA assay.  
     [0187] Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the corresponding ADAM or Interactor polypeptide to thereby isolate immunoglobulin library members that bind the polypeptide. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP™ Phage Display Kit, Catalog No. 240612).  
     [0188] Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, Ladner et al. U.S. Pat. No. 5,223,409; Kang et al. PCT International Publication No. WO 92/18619; Dower et al. PCT International Publication No. WO 91/17271; Winter et al. PCT International Publication WO 92/20791; Markland et al. PCT International Publication No. WO 92/15679; Breitling et al. PCT International Publication WO 93/01288; McCafferty et al. PCT International Publication No. WO 92/01047; Garrard et al. PCT International Publication No. WO 92/09690; Ladner et al. PCT International Publication No. WO 90/02809; Fuchs et al., 1991,  Bio/Technology  9:1370-1372; Hay et al., 1992,  Hum. Antibod. Hybridomas  3:81-85; Huse et al., 1989,  Science  246:1275-1281; Griffiths et al., 1993,  EMBO J  12:725-734; Hawkins et al., 1992,  J. Mol. Biol.  226:889-896; Clarkson et al., 1991,  Nature  352:624-628; Gram et al., 1992,  PNAS  89:3576-3580; Garrad et al., 1991,  Bio/Technology  9:1373-1377; Hoogenboom et al., 1991,  Nuc. Acid Res.  19:4133-4137; Barbas et al., 1991,  PNAS  88:7978-7982; and McCafferty et al., 1990,  Nature  348:552-55.  
     [0189] Additionally, recombinant antibodies to an ADAM or Interactor polypeptide, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al. International Application No. PCT/US86/02269; Akira, et al. European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al. European Patent Application 173,494; Neuberger et al. PCT International Publication No. WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567; Cabilly et al. European Patent Application 125,023; Better et al., 1988,  Science  240:1041-1043; Liu et al., 1987,  PNAS  84:3439-3443; Liu et al., 1987,  J. Immunol.  139:3521-3526; Sun et al., 1987,  PNAS  84:214-218; Nishimura et al., 1987,  Canc. Res.  47:999-1005; Wood et al., 1985,  Nature  314:446-449; and Shaw et al., 1988,  J. Natl. Cancer Inst.  80:1553-1559; S. L. Morrison, 1985,  Science  229:1202-1207; Oi et al., 1986,  BioTechniques  4:214; Winter U.S. Pat. No. 5,225,539; Jones et al., 1986,  Nature  321:552-525; Verhoeyan et al., 1988,  Science  239:1534; and Bcidler et al., 1988,  J. Immunol.  141:4053-4060.  
     [0190] An antibody against an ADAM or Interactor polypeptide (e.g., monoclonal antibody) can be used to isolate the corresponding polypeptide by standard techniques, such as affinity chromatography or immunoprecipitation. For example, antibodies can facilitate the purification of a natural ADAM or Interactor gene polypeptide from cells and of a recombinantly produced ADAM or Interactor polypeptide or peptide expressed in host cells. In addition, an antibody that binds to an ADAM or Interactor polypeptide can be used to detect the corresponding protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the protein. Such antibodies can also be used diagnostically to monitor ADAM or Interactor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen as described in detail herein. In addition, antibodies to an ADAM or Interactor polypeptide can be used as therapeutics for the treatment of diseases related to asthma, atopy, inflammatory bowel disease and obesity.  
     LIGANDS  
     [0191] The ADAM or Interactor polypeptides, polynucleotides, variants, or fragments or portions thereof (e.g. Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ), can be used to screen for ligands (e.g., agonists, antagonists, or inhibitors) that modulate the levels or activity of the ADAM or Interactor polypeptide. In addition, these ADAM or Interactor molecules can be used to identify endogenous ligands that bind to ADAM or Interactor polypeptides or polynucleotides in the cell. In one aspect of the present invention, the full-length ADAM or Interactor polypeptide is used to identify ligands. Alternatively, variants or portions of an ADAM or Interactor polypeptide are used. Such portions may comprise, for example, one or more domains of the ADAM or Interactor polypeptide (e.g., intracellular, extracellular, SH3, fibronectin III repeat, cysteine-rich, and Ser/Thr-XXX-Val domains) disclosed herein. Of particular interest are screening assays that identify agents that have relatively low levels of toxicity in human cells. A wide variety of assays may be used for this purpose, including in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays, and the like.  
     [0192] Ligands that bind to the ADAM or Interactor polypeptides or polynucleotides of the invention are potentially useful in diagnostic applications and pharmaceutical compositions, as described in detail herein. Ligands may encompass numerous chemical classes, though typically they are organic molecules, e.g., small molecules. Preferably, small molecules have a molecular weight of less than 5000 daltons, more preferably, small molecules have a molecular weight of more than 50 and less than 2,500 daltons. Such molecules can comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. Useful molecules often comprise cyclical carbon or heterocyclic structures or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Such molecules can also comprise biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.  
     [0193] Ligands may include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., 1991,  Nature  354:82-84; Houghten et al., 1991,  Nature  354:84-86) and combinatorial chemistry-derived molecular libraries made of D- or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al, 1993,  Cell  72:767-778); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′) 2 , Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules.  
     [0194] Test agents useful for identifying ADAM or Interactor ligands can be obtained from a wide variety of sources including libraries of synthetic or natural compounds. Synthetic compound libraries are commercially available from, for example, Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.). A rare chemical library is available from Aldrich Chemical Company, Inc. (Milwaukee, Wis.). Natural compound libraries comprising bacterial, fungal, plant or animal extracts are available from, for example, Pan Laboratories (Bothell, WA). In addition, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides.  
     [0195] Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts can be readily produced. Methods for the synthesis of molecular libraries are readily available (see, e.g., DeWiff et al., 1993,  Proc. Nat. Acad. Sci. USA  90:6909; Erb et al., 1994,  Proc. Natl. Acad. Sci. USA  91:11422; Zuckermann et al., 1994,  J. Med. Chem.  37:2678; Cho et al., 1993,  Science  261:1303; Carell et al., 1994,  Angew. Chem. Int. Ed. Engl.  33:2059; Carell et al., 1994,  Angew. Chem. Int. Ed. Engl.  33:2061; and in Gallop et al., 1994,  J. Med. Chem.  37:1233). In addition, natural or synthetic compound libraries and compounds can be readily modified through conventional chemical, physical and biochemical means (see, e.g., Blondelle et al., 1996,  Trends in Biotech.  14:60), and may be used to produce combinatorial libraries. In another approach, previously identified pharmacological agents can be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, and the analogs can be screened for ADAM or Interactor gene-modulating activity.  
     [0196] Numerous methods for producing combinatorial libraries are known in the art, including those involving biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the ‘one-bead one-compound’ library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to polypeptide libraries, while the other four approaches are applicable to polypeptide, non-peptide oligomer, or small molecule libraries of compounds (K. S. Lam, 1997,  Anticancer Drug Des.  12:145).  
     [0197] Non-limiting examples of small molecules, small molecule libraries, combinatorial libraries, and screening methods are described in B. Seligmann, 1995, “Synthesis, Screening, Identification of Positive Compounds and Optimization of Leads from Combinatorial Libraries: Validation of Success” p. 69-70.  Symposium: Exploiting Molecular Diversity: Small Molecule Libraries for Drug Discovery,  La Jolla, Calif., Jan. 23-25, 1995 (conference summary available from Wendy Warr &amp; Associates, 6 Berwick Court, Cheshire, UK CW4 7HZ); E. Martin et al., 1995,  J. Med. Chem.  38:1431-1436; E. Martin et al., 1995, “Measuring diversity: Experimental design of combinatorial libraries for drug discovery” Abstract, ACS Meeting, Anaheim, Calif., COMP 32; and E. Martin, 1995, “Measuring Chemical Diversity: Random Screening or Rationale Library Design” p. 27-30,  Symposium: Exploiting Molecular Diversity: Small Molecule Libraries for Drug Discovery,  La Jolla, Calif. Jan. 23-25, 1995 (conference summary available from Wendy Warr &amp; Associates, 6 Berwick Court, Cheshire, UK CW4 7HZ).  
     [0198] Libraries may be screened in solution (e.g., Houghten, 1992,  Biotechniques  13:412-421), or on beads (Lam, 1991,  Nature  354:82-84), chips (Fodor, 1993,  Nature  364:555-556), bacteria or spores (Ladner U.S. Pat. No. 5,223,409), plasmids (Cull et al., 1992,  Proc. Natl. Acad. Sci. USA  89:1865-1869), or on phage (Scott and Smith, 1990,  Science  249:386-390; Devlin, 1990,  Science  249:404-406; Cwirla et al., 1990,  Proc. Natl. Acad. Sci. USA  97:6378-6382; Felici, 1991,  J. Mol. Biol.  222:301-310; Ladner, supra).  
     [0199] Where the screening assay is a binding assay, an ADAM or Interactor polypeptide, polynucleotide, analog, or fragment thereof, may be joined to a label, where the label can directly or indirectly provide a detectable signal. Various labels include radioisotopes, fluorescers, chemiluminescers, enzymes, specific binding molecules, particles, e.g., magnetic particles, and the like. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin, etc. For the specific binding members, the complementary member would normally be labeled with a molecule that provides for detection, in accordance with known procedures.  
     [0200] A variety of other reagents may be included in the screening assay. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc., that are used to facilitate optimal protein-protein binding or reduce non-specific or background interactions. Reagents that improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The components are added in any order that produces the requisite binding. Incubations are performed at any temperature that facilitates optimal activity, typically between 40 and 40° C. Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high-throughput screening. Normally, between 0.1 and 1 hr will be sufficient. In general, a plurality of assay mixtures is run in parallel with different agent concentrations to obtain a differential response to these concentrations. Typically, one of these concentrations serves as a negative control, i.e., at zero concentration or below the level of detection.  
     [0201] To perform cell-free ligand screening assays, it may be desirable to immobilize either an ADAM or Interactor polypeptide, polynucleotide, or fragment to a surface to facilitate identification of ligands that bind to these molecules, as well as to accommodate automation of the assay. For example, a fusion protein comprising an ADAM or Interactor polypeptide and an affinity tag can be produced. In one embodiment, a glutathione-S-transferase/phosphodiesterase fusion protein comprising an ADAM or Interactor polypeptide is adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione-derivatized microtiter plates. Cell lysates (e.g., containing  35 S-labeled polypeptides) are added to the coated beads under conditions to allow complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the coated beads are washed to remove any unbound polypeptides, and the amount of immobilized radiolabel is determined. Alternatively, the complex is dissociated and the radiolabel present in the supernatant is determined. In another approach, the beads are analyzed by SDS-PAGE to identify the bound polypeptides.  
     [0202] Ligand-binding assays can be used to identify agonist or antagonists that alter the function or levels of an ADAM or Interactor polypeptide. Such assays are designed to detect the interaction of test agents (e.g., small molecules) with ADAM or Interactor polypeptides, polynucleotides, analogs, or fragments or portions thereof. Interactions may be detected by direct measurement of binding. Alternatively, interactions may be detected by indirect indicators of binding, such as stabilization/destabilization of protein structure, or activation/inhibition of biological function. Non-limiting examples of useful ligand-binding assays are detailed below.  
     [0203] Ligands that bind to ADAM or Interactor polypeptides, polynucleotides, analogs, or fragments or portions thereof, can be identified using real-time Bimolecular Interaction Analysis (BIA; Sjolander et al., 1991,  Anal. Chem.  63:2338-2345; Szabo et al., 1995,  Curr. Opin. Struct. Biol.  5:699-705). BIA-based technology (e.g., BIAcore™; LKB Pharmacia, Sweden) allows study of biospecific interactions in real time, without labeling. In BIA, changes in the optical phenomenon surface plasmon resonance (SPR) is used determine real-time interactions of biological molecules.  
     [0204] Ligands can also be identified by scintillation proximity assays (SPA, described in U.S. Pat. No. 4,568,649). In a modification of this assay that is currently undergoing development, chaperoning are used to distinguish folded and unfolded proteins. A tagged protein is attached to SPA beads, and test agents are added. The bead is then subjected to mild denaturing conditions (such as, e.g., heat, exposure to SDS, etc.) and a purified labeled chaperonin is added. If a test agent binds to a target, the labeled chaperonin will not bind; conversely, if no test agent binds, the protein will undergo some degree of denaturation and the chaperonin will bind.  
     [0205] Ligands can also be identified using a binding assay based on mitochondrial targeting signals (Hurt et al., 1985,  EMBO J.  4:2061-2068; Eilers and Schatz, 1986,  Nature  322:228-231). In a mitochondrial import assay, expression vectors are constructed in which nucleic acids encoding particular target proteins are inserted downstream of sequences encoding mitochondrial import signals. The chimeric proteins are synthesized and tested for their ability to be imported into isolated mitochondria in the absence and presence of test compounds. A test compound that binds to the target protein should inhibit its uptake into isolated mitochondria in vitro.  
     [0206] The ligand-binding assay described in Fodor et al., 1991,  Science  251:767-773, which involves testing the binding affinity of test compounds for a plurality of defined polymers synthesized on a solid substrate, can also be used.  
     [0207] Ligands that bind to ADAM or Interactor polypeptides or peptides can be identified using two-hybrid assays (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al., 1993,  Cell  72:223-232; Madura et al., 1993,  J. Biol. Chem.  268:12046-12054; Bartel et al., 1993,  Biotechniques  14:920-924; Iwabuchi et al., 1993,  Oncogene  8:1693-1696; and Brent WO 94/10300). The two-hybrid system relies on the reconstitution of transcription activation activity by association of the DNA-binding and transcription activation domains of a transcriptional activator through protein-protein interaction. The yeast GAL4 transcriptional activator may be used in this way, although other transcription factors have been used and are well known in the art. To carryout the two-hybrid assay, the GAL4 DNA-binding domain, and the GAL4 transcription activation domain are expressed, separately, as fusions to potential interacting polypeptides.  
     [0208] In one embodiment, the “bait” protein comprises an ADAM or Interactor polypeptide fused to the GAL4 DNA-binding domain. The “fish” protein comprises, for example, a human cDNA library encoded polypeptide fused to the GAL4 transcription activation domain. If the two, coexpressed fusion proteins interact in the nucleus of a host cell, a reporter gene (e.g., LacZ) is activated to produce a detectable phenotype. The host cells that show two-hybrid interactions can be used to isolate the containing plasmids containing the cDNA library sequences. These plasmids can be analyzed to determine the nucleic acid sequence and predicted polypeptide sequence of the candidate ligand. Alternatively, methods such as the three-hybrid (Licitra et al., 1996,  Proc. Nat. Acad. Sci. USA  93:12817-12821), and reverse two-hybrid (Vidal et al., 1996,  Proc. Natl. Acad. Sci. USA  93:10315-10320) systems may be used. Commercially available two-hybrid systems such as the CLONTECH Matchmaker™ systems and protocols (CLONTECH Laboratories, Inc., Palo Alto, Calif.) may be also be used (see also, A. R. Mendelsohn et al., 1994,  Curr. Op. Biotech.  5:482; E. M. Phizicky et al., 1995,  Microbiological Rev.  59:94; M. Yang et al., 1995,  Nucleic Acids Res.  23:1152; S. Fields et al., 1994,  Trends Genet.  10:286; and U.S. Pat. No. 6,283,173 and 5,468,614).  
     [0209] Several methods of automated assays have been developed in recent years so as to permit screening of tens of thousands of test agents in a short period of time. High-throughput screening methods are particularly preferred for use with the present invention. The ligand-binding assays described herein can be adapted for high-throughput screens, or alternative screens may be employed. For example, continuous format high throughput screens (CF-HTS) using at least one porous matrix allows the researcher to test large numbers of test agents for a wide range of biological or biochemical activity (see U.S. Pat. No. 5,976,813 to Beutel et al.). Moreover, CF-HTS can be used to perform multi-step assays.  
     DIAGNOSTICS  
     [0210] As discussed herein, ADAM or Interactor genes are associated with various diseases and disorders, including but not limited to, asthma, atopy, obesity, and inflammatory bowel disease. The present invention therefore provides nucleic acids and antibodies that can be useful in diagnosing individuals with disorders associated with aberrant ADAM or Interactor gene expression or mutated ADAM or Interactor genes. In particular, nucleic acids comprising ADAM or Interactor SNP alleles and haplotypes can be used to identify chromosomal abnormalities linked to these diseases. Additionally, antibodies directed against the amino acid variants encoded by the ADAM or Interactor SNPs can be used to identify disease-associated polypeptides. Examples 5 and 6 herein further illustrate the use of ADAM and Interactor genes for identifying polymorphisms.  
     [0211] Antibody-based diagnostic methods: In a further embodiment of the present invention, antibodies which specifically bind to an ADAM or Interactor polypeptide encoded by the nucleic acids shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , may be used for the diagnosis of conditions or diseases characterized by underexpression or overexpression of the ADAM or Interactor polynucleotide or polypeptide, or in assays to monitor patients being treated with an ADAM or Interactor polypeptide, polynucleotide, or antibody, or an ADAM or Interactor agonist, antagonist, or inhibitor.  
     [0212] The antibodies useful for diagnostic purposes may be prepared in the same manner as those for use in therapeutic methods, described herein. Antibodies may be raised to a full-length ADAM or Interactor polypeptide sequence. Alternatively, the antibodies may be raised to portions or variants of the ADAM or Interactor polypeptide. Such variants include polypeptides encoded by the disclosed ADAM or Interactor SNPs or alternate splice variants. In one aspect of the invention, antibodies are prepared to bind to an ADAM or Interactor polypeptide fragment comprising one or more domains of the ADAM or Interactor polypeptide (e.g., transmembrane, intracellular, extracellular, SH3, fibronectin III repeat, cysteine-rich, and Ser/Thr-XXX-Val domains), as described in detail herein.  
     [0213] Diagnostic assays for an ADAM or Interactor polypeptide include methods that utilize the antibody and a label to detect the protein in biological samples (e.g., human body fluids, cells, tissues, or extracts of cells or tissues). The antibodies may be used with or without modification, and may be labeled by joining them, either covalently or non-covalently, with a reporter molecule. A wide variety of reporter molecules that are known in the art may be used, several of which are described herein.  
     [0214] The invention provides methods for detecting disease-associated antigenic components in a biological sample, which methods comprise the steps of: 1) contacting a sample suspected to contain a disease-associated antigenic component with an antibody specific for an disease-associated antigen, extracellular or intracellular, under conditions in which an antigen-antibody complex can form between the antibody and disease-associated antigenic components in the sample; and 2) detecting any antigen-antibody complex formed in step (1) using any suitable means known in the art, wherein the detection of a complex indicates the presence of disease-associated antigenic components in the sample. It will be understood that assays that utilize antibodies directed against altered ADAM or Interactor amino acid sequences (i.e., epitopes encoded by SNPs, modifications, mutations, or variants) are within the scope of the invention.  
     [0215] Many immunoassay formats are known in the art, and the particular format used is determined by the desired application. An immunoassay can use, for example, a monoclonal antibody directed against a single disease-associated epitope, a combination of monoclonal antibodies directed against different epitopes of a single disease-associated antigenic component, monoclonal antibodies directed towards epitopes of different disease-associated antigens, polyclonal antibodies directed towards the same disease-associated antigen, or polyclonal antibodies directed towards different disease-associated antigens. Protocols can also, for example, use solid supports, or may involve immunoprecipitation.  
     [0216] In accordance with the present invention, “competitive” (U.S. Pat. Nos. 3,654,090 and 3,850,752), “sandwich” (U.S. Pat. No. 4,016,043), and “double antibody,” or “DASP” assays may be used. Several procedures for measuring the amount of an ADAM or Interactor polypeptide in a sample (e.g., ELISA, RIA, and FACS) are known in the art and provide a basis for diagnosing altered or abnormal levels of ADAM or Interactor polypeptide expression. Normal or standard values for an ADAM or Interactor polypeptide expression are established by incubating biological samples taken from normal subjects, preferably human, with antibody to an ADAM or Interactor polypeptide under conditions suitable for complex formation. The amount of standard complex formation may be quantified by various methods; photometric means are preferred. Levels of the ADAM or Interactor polypeptide expressed in the subject sample, negative control (normal) sample, and positive control (disease) sample are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.  
     [0217] Typically, immunoassays use either a labeled antibody or a labeled antigenic component (i.e., to compete with the antigen in the sample for binding to the antibody). A number of fluorescent materials are known and can be utilized as labels for antibodies or polypeptides. These include, for example, Cy3, Cy5, GFP (e.g., EGFP, DsRed, dEFP, etc. (CLONTECH, Palo Alto, Calif.)), Alexa, BODIPY, fluorescein (e.g., FluorX, DTAF, and FITC), rhodamine (e.g., TRITC), auramine, Texas Red, AMCA blue, and Lucifer Yellow. Antibodies or polypeptides can also be labeled with a radioactive element or with an enzyme. Preferred isotopes include  3 H,  14 C, 32 P,  35 S,  36 Cl,  51 Cr,  57 CO,  58 CO,  59 Fe,  90 Y,  125 I,  131 I, and  186 Re.  
     [0218] Preferred enzymes include peroxidase, β-glucuronidase, β-D-glucosidase, β-D-galactosidase, urease, glucose oxidase plus peroxidase, and alkaline phosphatase (see, e.g., U.S. Pat. Nos. 3,654,090; 3,850,752 and 4,016,043). Enzymes can be conjugated by reaction with bridging molecules such as carbodiimides, diisocyanates, glutaraldehyde, and the like. Enzyme labels can be detected visually, or measured by calorimetric, spectrophotometric, fluorospectrophotometric, amperometric, or gasometric techniques. Other labeling systems, such as avidin/biotin, Tyramide Signal Amplification (TSA™), are known in the art, and are commercially available (see, e.g., ABC kit, Vector Laboratories, Inc., Burlingame, Calif.; NEN® Life Science Products, Inc., Boston, Mass.).  
     [0219] Kits suitable for antibody-based diagnostic applications typically include one or more of the following components:  
     [0220] (1) Antibodies: The antibodies may be pre-labeled; alternatively, the antibody may be unlabeled and the ingredients for labeling may be included in the kit in separate containers, or a secondary, labeled antibody is provided; and  
     [0221] (2) Reaction components: The kit may also contain other suitably packaged reagents and materials needed for the particular immunoassay protocol, including solid-phase matrices, if applicable, and standards.  
     [0222] The kits referred to above may include instructions for conducting the test. Furthermore, in preferred embodiments, the diagnostic kits are adaptable to high-throughput or automated operation.  
     [0223] Nucleic-acid-based diagnostic methods: The invention provides methods for detecting altered levels or sequences of ADAM or Interactor nucleic acids (e.g., such as the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ) in a sample, such as in a biological sample, comprising the steps of: 1) contacting a sample suspected to contain a disease-associated nucleic acid with one or more disease-associated nucleic acid probes under conditions in which hybrids can form between any of the probes and disease-associated nucleic acid in the sample; and 2) detecting any hybrids formed in step (1) using any suitable means known in the art, wherein the detection of hybrids indicates the presence of the disease-associated nucleic acid in the sample. Exemplary methods are described in the Examples, herein below. To detect disease-associated nucleic acids present in low levels in biological samples, it may be necessary to amplify the disease-associated sequences or the hybridization signal as part of the diagnostic assay. Techniques for amplification are known to those of skill in the art.  
     [0224] The presence of an ADAM or Interactor polynucleotide sequences can be detected by DNA-DNA or DNA-RNA hybridization, or by amplification using probes or primers comprising at least a portion of an ADAM or Interactor polynucleotide, or a sequence complementary thereto. In particular, nucleic acid amplification-based assays can use ADAM or Interactor oligonucleotides or oligomers to detect transformants containing ADAM or Interactor DNA or RNA. Preferably, ADAM or Interactor nucleic acids useful as probes in diagnostic methods include oligonucleotides at least 15 contiguous nucleotides in length, more preferably at least 20 contiguous nucleotides in length, and most preferably at least 25-55 contiguous nucleotides in length, that hybridize specifically with ADAM or Interactor nucleic acids. As non-limiting examples, probes or primers useful for diagnostics may comprise any of the ADAM or Interactor DNA nucleotide sequences shown in Tables 3 and 4.  
     [0225] Several methods can be used to produce specific probes for ADAM or Interactor polynucleotides. For example, labeled probes can be produced by oligo-labeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide. Alternatively, ADAM or Interactor polynucleotide sequences, or any portions or fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase, such as T7, T3, or SP(6) end labeled nucleotides. These procedures may be conducted using a variety of commercially available kits (e.g., from Amersham-Pharmacia; Promega Corp.; and U.S. Biochemical Corp., Cleveland, Ohio). Suitable reporter molecules or labels which may be used include radionucleotides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.  
     [0226] A sample to be analyzed, such as, for example, a tissue sample (e.g., hair or buccal cavity) or body fluid sample (e.g., blood or saliva), may be contacted directly with the nucleic acid probes. Alternatively, the sample may be treated to extract the nucleic acids contained therein. It will be understood that the particular method used to extract DNA will depend on the nature of the biological sample. The resulting nucleic acid from the sample may be subjected to gel electrophoresis or other size separation techniques, or, the nucleic acid sample may be immobilized on an appropriate solid matrix without size separation.  
     [0227] Kits suitable for nucleic acid-based diagnostic applications typically include the following components:  
     [0228] (1)Probe DNA: The probe DNA may be prelabeled; alternatively, the probe DNA may be unlabeled and the ingredients for labeling may be included in the kit in separate containers; and  
     [0229] (2)Hybridization reagents: The kit may also contain other suitably packaged reagents and materials needed for the particular hybridization protocol, including solid-phase matrices, if applicable, and standards.  
     [0230] In cases where a disease condition is suspected to involve an alteration of an ADAM or Interactor nucleotide sequence, specific oligonucleotides may be constructed and used to assess the level of disease mRNA in cells affected or other tissue affected by the disease. For example, PCR can be used to test whether a person has a disease-related polymorphism (i.e., mutation). Specific methods of polymorphism identification are described herein, but are not intended to limit the present invention. The detection of polymorphisms in DNA sequences can be accomplished by a variety of methods including, but not limited to, RFLP detection based on allele-specific restriction-endonuclease cleavage (Kan and Dozy, 1978,  Lancet  ii:910-912), hybridization with allele-specific oligonucleotide probes (Wallace et al., 1978,  Nucl Acids Res.  6:3543-3557), including immobilized oligonucleotides (Saiki et al., 1969,  Proc. Natl. Acad. Sci. USA  86:6230-6234) or oligonucleotide arrays (Maskos and Southern, 1993,  Nucl. Acids Res.  21:2269-2270), allele-specific PCR (Newton et al., 1989,  Nucl. Acids Res.  17:2503-2516), mismatch-repair detection (MRD) (Faham and Cox, 1995,  Genome Res.  5:474-482), binding of MutS protein (Wagner et al., 1995,  Nucl. Acids Res.  23:3944-3948), denaturing-gradient gel electrophoresis (DGGE) (Fisher and Lerman et al., 1983,  Proc. Natl. Acad. Sci. USA.  80:1579-1583), single-strand-conformation-polymorphism detection (Orita et al., 1983,  Genomics  5:874-879), RNAase cleavage at mismatched base-pairs (Myers et al., 1985,  Science  230:1242), chemical (Cotton et al., 1988,  Proc. Natl. Acad. Sci. USA  8:4397-4401) or enzymatic (Youil et al., 1995,  Proc. Natl. Acad. Sci. USA  92:87-91) cleavage of heteroduplex DNA, methods based on allele specific primer extension (Syvanen et al., 1990,  Genomics  8:684-692), genetic bit analysis (GBA) Nikiforov et al., 1994,  Nucl. Acids  22:4167-4175), the oligonucleotide-ligation assay (OLA) (Landegren et al., 1988, Science 241:1077), the allele-specific ligation chain reaction (LCR) (Barrany, 1991,  Proc. Natl. Acad. Sci. USA  88:189-193), gap-LCR (Abravaya et al., 1995,  Nucl. Acids Res.  23:675-682), radioactive or fluorescent DNA sequencing using standard procedures well known in the art, and peptide nucleic acid (PNA) assays (Orum et al., 1993,  Nucl. Acids Res.  21:5332-5356).  
     [0231] For PCR analysis, ADAM or Interactor oligonucleotides may be chemically synthesized, generated enzymatically, or produced from a recombinant source. Oligomers will preferably comprise two nucleotide sequences, one with a sense orientation (5′→3′) and another with an antisense orientation (3′→5′), employed under optimized conditions for identification of a specific gene or condition. The same two oligomers, nested sets of oligomers, or even a degenerate pool of oligomers may be employed under less stringent conditions for detection and quantification of closely related DNA or RNA sequences.  
     [0232] In accordance with PCR analysis, two oligonucleotides are synthesized by standard methods or are obtained from a commercial supplier of custom-made oligonucleotides. The length and base composition are determined by standard criteria using the Oligo 4.0 primer Picking program (W. Rychlik, 1992; available from Molecular Biology Insights, Inc., Cascade, Colo.). One of the oligonucleotides is designed so that it will hybridize only to the disease gene DNA under the PCR conditions used. The other oligonucleotide is designed to hybridize a segment of genomic DNA such that amplification of DNA using these oligonucleotide primers produces a conveniently identified DNA fragment. Samples may be obtained from hair follicles, whole blood, or the buccal cavity. The DNA fragment generated by this procedure is sequenced by standard techniques.  
     [0233] In one particular aspect, ADAM or Interactor oligonucleotides can be used to perform Genetic Bit Analysis (GBA) of ADAM or Interactor genes in accordance with published methods (T. T. Nikiforov et al., 1994,  Nucleic Acids Res.  22(20):4167-75; T. T. Nikiforov T T et al., 1994,  PCR Methods Appl.  3(5):285-91). In PCR-based GBA, specific fragments of genomic DNA containing the polymorphic site(s) are first amplified by PCR using one unmodified and one phosphorothioate-modified primer. The double-stranded PCR product is rendered single-stranded and then hybridized to immobilized oligonucleotide primer in wells of a multi-well plate. The primer is designed to anneal immediately adjacent to the polymorphic site of interest. The 3′ end of the primer is extended using a mixture of individually labeled dideoxynucleoside triphosphates. The label on the extended base is then determined. Preferably, GBA is performed using semi-automated ELISA or biochip formats (see, e.g., S. R. Head et al., 1997,  Nucleic Acids Res.  25(24):5065-71; T. T. Nikiforov et al., 1994,  Nucleic Acids Res.  22(20):4167-75).  
     [0234] Other amplification techniques besides PCR may be used as alternatives, such as ligation-mediated PCR or techniques involving Q-beta replicase (Cahill et al., 1991,  Clin. Chem.,  37(9):1482-5). Products of amplification can be detected by agarose gel electrophoresis, quantitative hybridization, or equivalent techniques for nucleic acid detection known to one skilled in the art of molecular biology (Sambrook et al., 1989). Other alterations in the disease gene may be diagnosed by the same type of amplification-detection procedures, by using oligonucleotides designed to contain and specifically identify those alterations.  
     [0235] In accordance with the present invention, ADAM or Interactor polynucleotides may also be used to detect and quantify levels of ADAM or Interactor mRNA in biological samples in which altered expression of ADAM or Interactor polynucleotide may be correlated with disease. These diagnostic assays may be used to distinguish between the absence, presence, increase, and decrease of ADAM or Interactor mRNA levels, and to monitor regulation of ADAM or Interactor polynucleotide levels during therapeutic treatment or intervention. For example, ADAM or Interactor polynucleotide sequences, or fragments, or complementary sequences thereof, can be used in Southern or Northern analysis, dot blot, or other membrane-based technologies; in PCR technologies; or in dip stick, pin, ELISA or biochip assays utilizing fluids or tissues from patient biopsies to detect the status of, e.g., levels or overexpression of ADAM or Interactor genes, or to detect altered ADAM or Interactor gene expression. Such qualitative or quantitative methods are well known in the art (G. H. Keller and M. M. Manak, 1993, DNA Probes, 2 nd  Ed, Macmillan Publishers Ltd., England; D. W. Dieffenbach and G. S. Dveksler, 1995,  PCR Primer: A Laboratory Manual,  Cold Spring Harbor Press, Plainview, N.Y.; B. D. Hames and S. J. Higgins, 1985,  Gene Probes  1, 2, IRL Press at Oxford University Press, Oxford, England).  
     [0236] Methods suitable for quantifying the expression of ADAM or Interactor genes include radiolabeling or biotinylating nucleotides, co-amplification of a control nucleic acid, and standard curves onto which the experimental results are interpolated (P. C. Melby et al., 1993,  J. Immunol. Methods  159:235-244; and C. Duplaa et al., 1993,  Anal. Biochem.  212(1):229-36.). The speed of quantifying multiple samples may be accelerated by running the assay in an ELISA format where the oligomer of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantification.  
     [0237] In accordance with these methods, the specificity of the probe, i.e., whether it is made from a highly specific region (e.g., at least 8 to 10 or 12 or 15 contiguous nucleotides in the 5′ regulatory region), or a less specific region (e.g., especially in the 3′ coding region), and the stringency of the hybridization or amplification (e.g., high, moderate, or low) will determine whether the probe identifies naturally occurring sequences encoding the ADAM or Interactor polypeptide, or alleles, SNPs, SNP alleles and haplotypes, mutants, or related sequences.  
     [0238] In a particular aspect, an ADAM or Interactor nucleic acid sequence (e.g., such as shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ), or a sequence complementary thereto, or fragment thereof, may be useful in assays that detect ADAM or Interactor-related diseases such as asthma. An ADAM or Interactor polynucleotide can be labeled by standard methods, and added to a biological sample from a subject under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample can be washed and the signal is quantified and compared with a standard value. If the amount of signal in the test sample is significantly altered from that of a comparable negative control (normal) sample, the altered levels of an ADAM or Interactor nucleotide sequence can be correlated with the presence of the associated disease. Such assays may also be used to evaluate the efficacy of a particular prophylactic or therapeutic regimen in animal studies, in clinical trials, or for an individual patient.  
     [0239] To provide a basis for the diagnosis of a disease associated with altered expression of a ADAM or Interactor gene, a normal or standard profile for expression is established. This may be accomplished by incubating biological samples taken from normal subjects, either animal or human, with a sequence complementary to the ADAM or Interactor polynucleotide, or a fragment thereof, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with those from an experiment where a known amount of a substantially purified polynucleotide is used. Standard values obtained from normal samples may be compared with values obtained from samples from patients who are symptomatic for the disease. Deviation between standard and subject (patient) values is used to establish the presence of the condition.  
     [0240] Once the disease is diagnosed and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to evaluate whether the level of expression in the patient begins to approximate that which is observed in a normal individual. The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.  
     [0241] With respect to diseases such as asthma, the presence of an abnormal amount of an ADAM or Interactor transcript in a biological sample (e.g., body fluid, cells, tissues, or cell or tissue extracts) from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier, thereby preventing the development or further progression of the disease.  
     [0242] Microarrays: In another embodiment of the present invention, oligonucleotides, or longer fragments derived from an ADAM or Interactor polynucleotide sequence described herein may be used as targets in a microarray (e.g., biochip) system. The microarray can be used to monitor the expression level of large numbers of genes simultaneously (to produce a transcript image), and to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disease, to diagnose disease, and to develop and monitor the activities of therapeutic or prophylactic agents. Preparation and use of microarrays have been described in WO 95/11995 to Chee et al.; D. J. Lockhart et al., 1996,  Nature Biotechnology  14:1675-1680; M. Schena et al., 1996,  Proc. Natl. Acad. Sci. USA  93:10614-10619; U.S. Pat. No. 6,015,702 to P. Lal et al; J. Worley et al., 2000,  Microarray Biochip Technology,  M. Schena, ed., Biotechniques Book, Natick, Mass., pp. 65-86; Y. H. Rogers et al., 1999,  Anal. Biochem.  266(1):23-30; S.R. Head et al., 1999,  Mol. Cell. Probes.  13(2):81-7; S. J. Watson et al., 2000,  Biol. Psychiatry  48(12): 1147-56.  
     [0243] In one application of the present invention, microarrays containing arrays of ADAM or Interactor polynucleotide sequences can be used to measure the expression levels of ADAM or Interactor nucleic acids in an individual. In particular, to diagnose an individual with an ADAM or Interactor -related condition or disease, a sample from a human or animal (containing nucleic acids, e.g., mRNA) can be used as a probe on a biochip containing an array of ADAM or Interactor polynucleotides (e.g., DNA) in decreasing concentrations (e.g., 1 ng, 0.1 ng, 0.01 ng, etc.). The test sample can be compared to samples from diseased and normal samples. Biochips can also be used to identify ADAM or Interactor mutations or polymorphisms in a population, including but not limited to, deletions, insertions, and mismatches. For example, mutations can be identified by: 1) placing ADAM or Interactor polynucleotides of this invention onto a biochip; 2) taking a test sample (containing, e.g., mRNA) and adding the sample to the biochip; 3) determining if the test samples hybridize to the 12q23-qter polynucleotides attached to the chip under various hybridization conditions (see, e.g., V. R. Chechetkin et al., 2000,  J. Biomol. Struct. Dyn.  18(1):83-101). Alternatively microarray sequencing can be performed (see, e.g., E. P. Diamandis, 2000,  Clin. Chem.  46(10):1523-5).  
     [0244] Chromosome mapping: In another application of this invention, ADAM or Interactor nucleic acid sequences (e.g. such as those shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ), or complementary sequences, or fragments thereof, can be used as probes to map genomic sequences. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to human artificial chromosome constructions (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial PI constructions, or single chromosome cDNA libraries (see, e.g., C. M. Price, 1993,  Blood Rev.,  7:127-134; B. J. Trask, 1991,  Trends Genet  7:149-154).  
     [0245] In another of its aspects, the invention relates to a diagnostic kit for detecting an ADAM or Interactor polynucleotide or polypeptide as it relates to a disease or susceptibility to a disease, particularly asthma. Also related is a diagnostic kit that can be used to detect or assess asthma conditions. Such kits comprise one or more of the following:  
     [0246] (a) an ADAM or Interactor polynucleotide, preferably the nucleotide sequence of any of the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , or a fragment thereof; or  
     [0247] (b) a nucleotide sequence complementary to that of (a); or  
     [0248] (c) an ADAM or Interactor polypeptide, preferably the polypeptide of any of the sequences shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 , or a fragment thereof; or  
     [0249] (d) an antibody to an ADAM or Interactor polypeptide, preferably to the polypeptide of any one of the sequences shown in Tables 2-7, SEQ ID NOs: 1-9, and FIGS.  1 - 12 , or an antibody bindable fragment thereof. It will be appreciated that in any such kits, (a), (b), (c), or (d) may comprise a substantial component and that instructions for use can be included. The kits may also contain peripheral reagents such as buffers, stabilizers, etc.  
     [0250] The present invention also includes a test kit for genetic screening that can be utilized to identify mutations in ADAM or Interactor genes. By identifying patients with mutated ADAM or Interactor DNA and comparing the mutation to a database that contains known mutations in ADAM or Interactor and a particular condition or disease, identification and confirmation of, a particular condition or disease can be made. Accordingly, such a kit would comprise a PCR-based test that would involve transcribing the patients mRNA with a specific primer, and amplifying the resulting cDNA using another set of primers. The amplified product would be detectable by gel electrophoresis and could be compared with known standards for ADAM or Interactor genes. Preferably, this kit would utilize a patient&#39;s blood, serum, or saliva sample, and the DNA would be extracted using standard techniques. Primers flanking a known mutation would then be used to amplify a fragment of an ADAM or Interactor gene. The amplified piece would then be sequenced to determine the presence of a mutation.  
     [0251] Genomic Screening: Polymorphic genetic markers linked to a ADAM or Interactor genes can be used to predict susceptibility to the diseases genetically linked to that chromosomal region. Similarly, the identification of polymorphic genetic markers within ADAM or Interactor genes will allow the identification of specific allelic variants that are in linkage disequilibrium with other genetic lesions that affect one of the disease states discussed herein including respiratory disorders, obesity, and inflammatory bowel disease. SSCP (see below) allows the identification of polymorphisms within the genomic and coding region of the disclosed genes.  
     [0252] The present invention provides sequences for primers that can be used identify exons that contain SNPs, as well as sequences for primers that can be used to identify the sequence changes of the SNPs. In particular, Tables 3 and 4 show polymorphic primers, probes, or genetic markers within the ADAM or Interactor genes, which can be used to identify specific allelic variants that are in linkage disequilibrium with other genetic lesions that affect one of the disease states discussed herein, including asthma, atopy, obesity, and inflammatory bowel disease. Such markers can be used in conjunction with SSCP to identify polymorphisms within the genomic and coding region of the disclosed gene. In particular, Table 7 describes the specific methods used to identify the SNPs described herein.  
     [0253] This information can be used to identify additional SNPs and SNP alleles and haplotypes in accordance with the methods disclosed herein. Suitable methods for genomic screening have also been described by, e.g., Sheffield et al., 1995,  Genet.  4:1837-1844; LeBlanc-Straceski et al., 1994,  Genomics  19:341-9; Chen et al., 1995,  Genomics  25:1-8. In employing these methods, the disclosed reagents can be used to predict the risk for disease (e.g., respiratory disorders, obesity, and inflammatory bowel disease) in a population or individual.  
     THERAPEUTICS  
     [0254] As discussed herein, ADAM or Interactor genes are associated with various diseases and disorders, including but not limited to, asthma, atopy, obesity, and inflammatory bowel disease (B. Wallaert et al., 1995,  J. Exp. Med.  182:1897-1904). The present invention therefore provides compositions (e.g., pharmaceutical compositions) comprising ADAM and Interactor nucleic acids, polypeptides, antibodies, ligands, or variants, portions, or fragments thereof that can be useful in treating individuals with these disorders. Also provided are methods employing ADAM or Interactor nucleic acids, polypeptides, antibodies, ligands, or variants, portions, or fragments thereof to identify drug candidates that can be used to prevent, treat, or ameliorate such disorders.  
     [0255] Drug screening and design: The present invention provides methods of screening for drugs using an ADAM or Interactor polypeptide, or portion thereof, in competitive binding assays, according to methods well-known in the art. For example, competitive drug screening assays can be employed using neutralizing antibodies capable of specifically binding an ADAM or Interactor polypeptide compete with a test compound for binding to the ADAM or Interactor polypeptide or fragments thereof.  
     [0256] The present invention further provides methods of rational drug design employing an ADAM or Interactor polypeptide, antibody, or portion or functional equivalent thereof. The goal of rational drug design is to produce structural analogs of biologically active polypeptides of interest or of small molecules with which they interact (e.g., agonists, antagonists, or inhibitors). In turn, these analogs can be used to fashion drugs which are, for example, more active or stable forms of the polypeptide, or which, e.g., enhance or interfere with the function of the polypeptide in vivo (see, e.g., Hodgson, 1991,  Bio/Technology,  9:19-21). An example of rational drug design is the development of HIV protease inhibitors (Erickson et al., 1990,  Science,  249:527-533).  
     [0257] In one approach, one first determines the three-dimensional structure of a protein of interest or, for example, of an ADAM or Interactor polypeptide or ligand complex, by x-ray crystallography, computer modeling, or a combination thereof. Useful information regarding the structure of a polypeptide can also be gained by computer modeling based on the structure of homologous proteins. In addition, ADAM or Interactor polypeptides, or portions thereof, can be analyzed by an alanine scan (Wells, 1991,  Methods in Enzymol.,  202:390-411). In this technique, each amino acid residue in an ADAM or Interactor polypeptide is replaced by alanine, and its effect on the activity of the polypeptide is determined.  
     [0258] In another approach, an antibody specific to an ADAM or Interactor polypeptide can be isolated, selected by a functional assay, and then analyzed to solve its crystal structure. In principle, this approach can yield a pharmacore upon which subsequent drug design can be based. Alternatively, it is possible to bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids is predicted to be an analog of the corresponding ADAM or Interactor polypeptide. The anti-id can then be used to identify and isolate peptides from banks of chemically or biologically produced banks of peptides. Selected peptides can subsequently be used as pharmacores.  
     [0259] Non-limiting examples of methods and computer tools for drug design are described in R. Cramer et al., 1974,  J. Med. Chem.  17:533; H. Kubinyi (ed) 1993, 3 D QSAR in Drug Design, Theory, Methods, and Applications,  ESCOM, Leiden, Holland; P. Dean (ed) 1995,  Molecular Similarity in Drug Design,  K. Kim “Comparative molecular field analysis (ComFA)” p. 291-324, Chapman &amp; Hill, London, UK; Y. et al., 1993,  J. Comp.—Aid. Mol. Des.  7:83-102; G. Lauri and P. A. Bartlett, 1994,  J. Comp.—Aid. Mol. Des.  8:51-66; P. J. Gane and P. M. Dean, 2000,  Curr. Opin. Struct. Biol.  10(4):401-4; H. O. Kim and M. Kahn, 2000,  Comb. Chem. High Throughput Screen.  3(3):167-83; G. K. Farber, 1999,  Pharmacol Ther.  84(3):327-32; and H. van de Waterbeemd (ed) 1996,  Structure - Property Correlations in Drug Research,  Academic Press, San Diego, Calif.  
     [0260] In another aspect of the present invention, cells and animals that carry an ADAM or Interactor gene or an analog thereof can be used as model systems to study and test for substances that have potential as therapeutic agents. After a test agent is administered to animals or applied to the cells, the phenotype of the animals/cells can be determined.  
     [0261] In accordance with these methods, one may design drugs that result in, for example, altered ADAM or Interactor polypeptide activity or stability. Such drugs may act as inhibitors, agonists, or antagonists of an ADAM or Interactor polypeptide. By virtue of the availability of cloned ADAM or Interactor gene sequences, sufficient amounts of the ADAM or Interactor polypeptide may be produced to perform such analytical studies as x-ray crystallography. In addition, the knowledge of the ADAM or Interactor polypeptide sequence will guide those employing computer-modeling techniques in place of, or in addition to x-ray crystallography.  
     [0262] Pharmaceutical compositions: The present invention contemplates compositions comprising a ADAM or Interactor polynucleotides, polypeptide, antibody, ligand (e.g., agonist, antagonist, or inhibitor), or fragments, variants, or analogs thereof, and a physiologically acceptable carrier, excipient, or diluent as described in detail herein. The present invention further contemplates pharmaceutical compositions useful in practicing the therapeutic methods of this invention. Preferably, a pharmaceutical composition includes, in admixture, a pharmaceutically acceptable excipient (carrier) and one or more of an ADAM or Interactor polypeptide, polynucleotide, ligand, antibody, or fragment, portion, or variant thereof, as described herein, as an active ingredient. The preparation of pharmaceutical compositions that contain ADAM or Interactor molecules as active ingredients is well understood in the art. Typically, such compositions are prepared as injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared. The preparation can also be emulsified. The active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH-buffering agents, which enhance the effectiveness of the active ingredient.  
     [0263] An ADAM or Interactor polypeptide, polynucleotide, ligand, antibody, or fragment, portion, or variant thereof can be formulated into the pharmaceutical composition as neutralized physiologically acceptable salt forms. Suitable salts include the acid addition salts (i.e., formed with the free amino groups of the polypeptide or antibody molecule) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.  
     [0264] The pharmaceutical compositions can be administered systemically by oral or parenteral routes. Non-limiting parenteral routes of administration include subcutaneous, intramuscular, intraperitoneal, intravenous, transdermal, inhalation, intranasal, intra-arterial, intrathecal, enteral, sublingual, or rectal. Intravenous administration, for example, can be performed by injection of a unit dose. The term “unit dose” when used in reference to a pharmaceutical composition of the present invention refers to physically discrete units suitable as unitary dosage for humans, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle.  
     [0265] In one particular embodiment of the present invention, the disclosed pharmaceutical compositions are administered via mucoactive aerosol therapy (see, e.g., M. Fuloria and B. K. Rubin, 2000,  Respir. Care  45:868-873; I. Gonda, 2000,  J. Pharm. Sci.  89:940-945; R. Dhand, 2000,  Curr. Opin. Pulm. Med.  6(1):59-70; B. K. Rubin, 2000,  Respir. Care  45(6):684-94; S. Suarez and A. J. Hickey, 2000,  Respir. Care.  45(6):652-66).  
     [0266] Pharmaceutical compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, capacity of the subject&#39;s immune system to utilize the active ingredient, and degree of modulation of ADAM or Interactor gene activity desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are specific for each individual. However, suitable dosages may range from about 0.1 to 20, preferably about 0.5 to about 10, and more preferably one to several, milligrams of active ingredient per kilogram body weight of individual per day and depend on the route of administration. Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration. Alternatively, continuous intravenous infusions sufficient to maintain concentrations of 10 nM to 10 μM in the blood are contemplated. An exemplary pharmaceutical formulation comprises: ADAM or Interactor antagonist or inhibitor (5.0 mg/ml); sodium bisulfite USP (3.2 mg/ml); disodium edetate USP (0.1 mg/ml); and water for injection q.s.a.d. (1.0 ml). As used herein, “pg” means picogram, “ng” means nanogram, “μg” means microgram, “mg” means milligram, “μl” means microliter, “ml” means milliliter, and “l” means L.  
     [0267] For further guidance in preparing pharmaceutical formulations, see, e.g., Gilman et al. (eds), 1990,  Goodman and Gilman&#39;s: The Pharmacological Basis of Therapeutics,  8th ed., Pergamon Press; and  Remington&#39;s Pharmaceutical Sciences,  17th ed., 1990, Mack Publishing Co., Easton, Pa.; Avis et al. (eds), 1993,  Pharmaceutical Dosage Forms: Parenteral Medications,  Dekker, New York; Lieberman et al. (eds), 1990,  Pharmaceutical Dosage Forms: Disperse Systems,  Dekker, New York.  
     [0268] In yet another aspect of this invention, antibodies that specifically react with an ADAM or Interactor polypeptide or peptides derived therefrom can be used as therapeutics. In particular, such antibodies can be used to block the activity of an ADAM or Interactor polypeptide. Antibodies or fragments thereof can be formulated as pharmaceutical compositions and administered to a subject. It is noted that antibody-based therapeutics produced from non-human sources can cause an undesired immune response in human subjects. To minimize this problem, chimeric antibody derivatives can be produced. Chimeric antibodies combine a non-human animal variable region with a human constant region. Chimeric antibodies can be constructed according to methods known in the art (see Morrison et al., 1985,  Proc. Natl. Acad. Sci. USA  81:6851; Takeda et al., 1985,  Nature  314:452; U.S. Pat. No. 4,816,567 of Cabilly et al.; U.S. Pat. No. 4,816,397 of Boss et al.; European Patent Publication EP 171496; EP 0173494; United Kingdom Patent GB 2177096B).  
     [0269] In addition, antibodies can be further “humanized” by any of the techniques known in the art, (e.g., Teng et al., 1983,  Proc. Natl. Acad. Sci. USA  80:7308-7312; Kozbor et al., 1983,  Immunology Today  4: 7279; Olsson et al., 1982,  Meth. Enzymol.  92:3-16; International Patent Application WO92/06193; EP 0239400). Humanized antibodies can also be obtained from commercial sources (e.g., Scotgen Limited, Middlesex, England). Immunotherapy with a humanized antibody may result in increased long-term effectiveness for the treatment of chronic disease situations or situations requiring repeated antibody treatments.  
     PHARMACOGENOMICS  
     [0270] Pharmacogenetics: The ADAM or Interactor polynucleotides and polypeptides (e.g., shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ) of the invention are also useful in pharmacogenetic analysis (i.e., the study of the relationship between an individual&#39;s genotype and that individual&#39;s response to a therapeutic composition or drug). See, e.g., M. Eichelbaum, 1996,  Clin. Exp. Pharmacol. Physiol.  23(10-11):983-985, and M. W. Linder, 1997,  Clin. Chem.  43(2):254-266. The genotype of the individual can determine the way a therapeutic acts on the body or the way the body metabolizes the therapeutic. Further, the activity of drug metabolizing enzymes affects both the intensity and duration of therapeutic activity. Differences in the activity or metabolism of therapeutics can lead to severe toxicity or therapeutic failure. Accordingly, a physician or clinician may consider applying knowledge obtained in relevant pharmacogenetic studies in determining whether to administer an ADAM or Interactor polypeptide, polynucleotide, analog, antagonist, inhibitor, or modulator, as well as tailoring the dosage and therapeutic or prophylactic treatment regimen.  
     [0271] In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions can be due to a single factor that alters the way the drug act on the body (altered drug action), or a factor that alters the way the body metabolizes the drug (altered drug metabolism). These conditions can occur either as rare genetic defects or as naturally-occurring polymorphisms. For example, glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common inherited enzymopathy which results in haemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.  
     [0272] The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. The gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response. This has been demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme, ultra-rapid metabolizers fail to respond to standard doses. Recent studies have determined that ultra-rapid metabolism is attributable to CYP2D6 gene amplification.  
     [0273] By analogy, genetic polymorphism or mutation may lead to allelic variants of ADAM or Interactor genes in the population which have different levels of activity. The ADAM or Interactor polypeptides or polynucleotides thereby allow a clinician to ascertain a genetic predisposition that can affect treatment modality. In addition, genetic mutation or variants at other genes may potentiate or diminish the activity of ADAM or Interactor-targeted drugs. Thus, in an ADAM or Interactor gene-based treatment, a polymorphism or mutation may give rise to individuals that are more or less responsive to treatment. Accordingly, dosage would necessarily be modified to maximize the therapeutic effect within a given population containing the polymorphism. As an alternative to genotyping, specific polymorphic polypeptides or polynucleotides can be identified.  
     [0274] To identify genes that modify ADAM or Interactor-targeted drug response, several pharmacogenetic methods can be used. One pharmacogenomics approach, “genome-wide association”, relies primarily on a high-resolution map of the human genome. This high-resolution map shows previously identified gene-related markers (e.g., a “bi-allelic” gene marker map which consists of 60,000-100,000 polymorphic or variable sites on the human genome, each of which has two variants). A high-resolution genetic map can then be compared to a map of the genome of each of a statistically significant number of patients taking part in a Phase II/III drug trial to identify markers associated with a particular observed drug response or side effect. Alternatively, a high-resolution map can be generated from a combination of some ten million known single nucleotide polymorphisms (SNPs) in the human genome. Given a genetic map based on the occurrence of such SNPs, individuals can be grouped into genetic categories depending on a particular pattern of SNPs in their individual genome. In this way, treatment regimens can be tailored to groups of genetically similar individuals, taking into account traits that may be common among such genetically similar individuals (see, e.g., D. R. Pfost et al., 2000,  Trends Biotechnol.  18(8):334-8).  
     [0275] As another example, the “candidate gene approach”, can be used. According to this method, if a gene that encodes a drug target is known, all common variants of that gene can be fairly easily identified in the population and it can be determined if having one version of the gene versus another is associated with a particular drug response.  
     [0276] As yet another example, a “gene expression profiling approach”, can be used. This method involves testing the gene expression of an animal treated with a drug (e.g., an ADAM or Interactor polypeptide, polynucleotide, analog, or modulator) to determine whether gene pathways related to toxicity have been turned on.  
     [0277] Information obtained from one of the approaches described herein can be used to establish a pharmacogenetic profile, which can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment an individual. A pharmacogenetic profile, when applied to dosing or drug selection, can be used to avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with an ADAM or Interactor polypeptide, polynucleotide, analog, antagonist, inhibitor, or modulator.  
     [0278] The ADAM or Interactor polypeptides or polynucleotides of the invention are also useful for monitoring therapeutic effects during clinical trials and other treatment. Thus, the therapeutic effectiveness of an agent that is designed to increase or decrease gene expression, polypeptide levels, or activity can be monitored over the course of treatment using the ADAM or Interactor compositions or modulators. For example, monitoring can be performed by: 1) obtaining a pre-administration sample from a subject prior to administration of the agent; 2) detecting the level of expression or activity of the protein in the pre-administration sample; 3) obtaining one or more post-administration samples from the subject; 4) detecting the level of expression or activity of the polypeptide in the post-administration samples; 5) comparing the level of expression or activity of the polypeptide in the pre-administration sample with the polypeptide in the post-administration sample or samples; and 6) increasing or decreasing the administration of the agent to the subject accordingly.  
     [0279] Gene Therapy: The ADAM or Interactor polynucleotides and polypeptides (e.g., shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ) of the invention also find use as gene therapy reagents. In recent years, significant technological advances have been made in the area of gene therapy for both genetic and acquired diseases (Kay et al., 1997,  Proc. Natl. Acad. Sci. USA,  94:12744-12746). Gene therapy can be defined as the transfer of DNA for therapeutic purposes. Improvement in gene transfer methods has allowed for development of gene therapy protocols for the treatment of diverse types of diseases. Gene therapy has also taken advantage of recent advances in the identification of new therapeutic genes, improvement in both viral and non-viral gene delivery systems, better understanding of gene regulation, and improvement in cell isolation and transplantation. Gene therapy would be carried out according to generally accepted methods as described by, for example, Friedman, 1991,  Therapy for Genetic Diseases,  Friedman, Ed., Oxford University Press, pages 105-121.  
     [0280] Vectors for introduction of genes both for recombination and for extrachromosomal maintenance are known in the art, and any suitable vector may be used. Methods for introducing DNA into cells such as electroporation, calcium phosphate co-precipitation, and viral transduction are known in the art, and the choice of method is within the competence of one skilled in the art (Robbins (ed), 1997,  Gene Therapy Protocols,  Human Press, NJ). Cells transformed with an ADAM or Interactor gene can be used as model systems to study asthma and other related disorders and to identify drug treatments for the treatment of such disorders.  
     [0281] Gene transfer systems known in the art may be useful in the practice of the gene therapy methods of the present invention. These include viral and non-viral transfer methods. A number of viruses have been used as gene transfer vectors, including polyoma, i.e., SV40 (Madzak et al., 1992,  J. Gen. Virol.,  73:1533-1536), adenovirus (Berkner, 1992,  Curr. Top. Microbiol. Immunol.,  158:39-6; Berkner et al., 1988,  Bio Techniques,  6:616-629; Gorziglia et al., 1992,  J. Virol.,  66:4407-4412; Quantin et al., 1992,  Proc. Natl. Acad. Sci. USA,  89:2581-2584; Rosenfeld et al., 1992,  Cell,  68:143-155; Wilkinson et al., 1992,  Nucl. Acids Res.,  20:2233-2239; Stratford-Perricaudet et al., 1990,  Hum. Gene Ther.,  1:241-256), vaccinia virus (Mackett et al., 1992,  Biotechnology,  24:495-499), adeno-associated virus (Muzyczka, 1992,  Curr. Top. Microbiol. Immunol.,  158:91-123; Ohi et al., 1990,  Gene,  89:279-282), herpes viruses including HSV and EBV (Margolskee, 1992,  Curr. Top. Microbiol. Immunol.,  158:67-90; Johnson et al., 1992,  J. Virol.,  66:2952-2965; Fink et al., 1992,  Hum. Gene Ther.,  3:11-19; Breakfield et al., 1987,  Mol. Neurobiol.,  1:337-371; Fresse et al., 1990,  Biochem. Pharmacol.,  40:2189-2199), and retroviruses of avian (Brandyopadhyay et al., 1984,  Mol. Cell Biol.,  4:749-754; Petropouplos et al., 1992,  J. Virol.,  66:3391-3397), murine (Miller, 1992,  Curr. Top. Microbiol. Immunol.,  158:1-24; Miller et al., 1985,  Mol. Cell Biol.,  5:431-437; Sorge et al., 1984,  Mol. Cell Biol.,  4:1730-1737; Mann et al., 1985,  J. Virol.,  54:401-407), and human origin (Page et al., 1990,  J. Virol.,  64:5370-5276; Buchschalcher et al., 1992,  J. Virol.,  66:2731-2739). Most human gene therapy protocols have been based on disabled murine retroviruses.  
     [0282] Non-viral gene transfer methods known in the art include chemical techniques such as calcium phosphate coprecipitation (Graham et al., 1973,  Virology,  52:456-467; Pellicer et al., 1980,  Science,  209:1414-1422), mechanical techniques, for example microinjection (Anderson et al., 1980,  Proc. Natl. Acad. Sci. USA,  77:5399-5403; Gordon et al., 1980,  Proc. Natl. Acad. Sci. USA,  77:7380-7384; Brinster et al., 1981,  Cell,  27:223-231; Constantini et al., 1981,  Nature,  294:92-94), membrane fusion-mediated transfer via liposomes (Felgner et al., 1987,  Proc. Natl. Acad. Sci. USA,  84:7413-7417; Wang et al., 1989,  Biochemistry,  28:9508-9514; Kaneda et al., 1989,  J. Biol. Chem.,  264:12126-12129; Stewart et al., 1992,  Hum. Gene Ther.,  3:267-275; Nabel et al., 1990,  Science,  249:1285-1288; Lim et al., 1992,  Circulation,  83:2007-2011), and direct DNA uptake and receptor-mediated DNA transfer (Wolff et al., 1990,  Science,  247:1465-1468; Wu et al., 1991,  BioTechniques,  11:474-485; Zenke et al., 1990,  Proc. Natl. Acad. Sci. USA,  87:3655-3659; Wu et al., 1989,  J. Biol. Chem.,  264:16985-16987; Wolff et al., 1991,  BioTechniques,  11:474-485; Wagner et al., 1991,  Proc. Natl. Acad. Sci. USA,  88:4255-4259; Cotten et al., 1990,  Proc. Natl. Acad. Sci. USA,  87:4033-4037; Curiel et al., 1991,  Proc. Natl. Acad. Sci. USA,  88:8850-8854; Curiel et al., 1991,  Hum. Gene Ther.,  3:147-154).  
     [0283] In one approach, plasmid DNA is complexed with a polylysine-conjugated antibody specific to the adenovirus hexon protein, and the resulting complex is bound to an adenovirus vector. The trimolecular complex is then used to infect cells. The adenovirus vector permits efficient binding, internalization, and degradation of the endosome before the coupled DNA is damaged. In another approach, liposome/DNA is used to mediate direct in vivo gene transfer. While in standard liposome preparations the gene transfer process is non-specific, localized in vivo uptake and expression have been reported in tumor deposits, for example, following direct in situ administration (Nabel, 1992,  Hum. Gene Ther.,  3:399-410).  
     [0284] Suitable gene transfer vectors possess a promoter sequence, preferably a promoter that is cell-specific and placed upstream of the sequence to be expressed. The vectors may also contain, optionally, one or more expressible marker genes for expression as an indication of successful transfection and expression of the nucleic acid sequences contained in the vector. In addition, vectors can be optimized to minimize undesired immunogenicity and maximize long-term expression of the desired gene product(s) (see Nabe, 1999,  Proc. Natl. Acad. Sci. USA  96:324-326). Moreover, vectors can be chosen based on cell-type that is targeted for treatment. Notably, gene transfer therapies have been initiated for the treatment of various pulmonary diseases (see, e.g., M. J. Welsh, 1999,  J. Clin. Invest.  104(9):1165-6; D. L. Ennist, 1999,  Trends Pharmacol. Sci.  20:260-266; S. M. Albelda et al., 2000,  Ann. Intern. Med.  132:649-660; E. Alton and C. Kitson C., 2000,  Expert Opin. Investig. Drugs.  9(7):1523-35).  
     [0285] Illustrative examples of vehicles or vector constructs for transfection or infection of the host cells include replication-defective viral vectors, DNA virus or RNA virus (retrovirus) vectors, such as adenovirus, herpes simplex virus and adeno-associated viral vectors. Adeno-associated virus vectors are single stranded and allow the efficient delivery of multiple copies of nucleic acid to the cell&#39;s nucleus. Preferred are adenovirus vectors. The vectors will normally be substantially free of any prokaryotic DNA and may comprise a number of different functional nucleic acid sequences. An example of such functional sequences may be a DNA region comprising transcriptional and translational initiation and termination regulatory sequences, including promoters (e.g., strong promoters, inducible promoters, and the like) and enhancers which are active in the host cells. Also included as part of the functional sequences is an open reading frame (polynucleotide sequence) encoding a protein of interest. Flanking sequences may also be included for site-directed integration. In some situations, the 5′-flanking sequence will allow homologous recombination, thus changing the nature of the transcriptional initiation region, so as to provide for inducible or non-inducible transcription to increase or decrease the level of transcription, as an example.  
     [0286] In general, the encoded and expressed ADAM or Interactor polypeptide may be intracellular, i.e., retained in the cytoplasm, nucleus, or in an organelle, or may be secreted by the cell. For secretion, the natural signal sequence present in an ADAM or Interactor polypeptide may be retained. When the polypeptide or peptide is a fragment of an ADAM or Interactor protein, a signal sequence may be provided so that, upon secretion and processing at the processing site, the desired protein will have the natural sequence. Specific examples of coding sequences of interest for use in accordance with the present invention include the ADAM or Interactor polypeptide-coding sequences disclosed herein.  
     [0287] As previously mentioned, a marker may be present for selection of cells containing the vector construct. The marker may be an inducible or non-inducible gene and will generally allow for positive selection under induction, or without induction, respectively. Examples of marker genes include neomycin, dihydrofolate reductase, glutamine synthetase, and the like. The vector employed will generally also include an origin of replication and other genes that are necessary for replication in the host cells, as routinely employed by those having skill in the art. As an example, the replication system comprising the origin of replication and any proteins associated with replication encoded by a particular virus may be included as part of the construct. The replication system must be selected so that the genes encoding products necessary for replication do not ultimately transform the cells. Such replication systems are represented by replication-defective adenovirus (see G. Acsadi et al., 1994,  Hum. Mol. Genet.  3:579-584) and by Epstein-Barr virus. Examples of replication defective vectors, particularly, retroviral vectors that are replication defective, are BAG, (see Price et al., 1987,  Proc. Natl. Acad. Sci. USA,  84:156; Sanes et al., 1986,  EMBO J.,  5:3133). It will be understood that the final gene construct may contain one or more genes of interest, for example, a gene encoding a bioactive metabolic molecule. In addition, cDNA, synthetically produced DNA or chromosomal DNA may be employed utilizing methods and protocols known and practiced by those having skill in the art.  
     [0288] According to one approach for gene therapy, a vector encoding an ADAM or Interactor polypeptide is directly injected into the recipient cells (in vivo gene therapy). Alternatively, cells from the intended recipients are explanted, genetically modified to encode an ADAM or Interactor polypeptide, and reimplanted into the donor (ex vivo gene therapy). An ex vivo approach provides the advantage of efficient viral gene transfer, which is superior to in vivo gene transfer approaches. In accordance with ex vivo gene therapy, the host cells are first transfected with engineered vectors containing at least one gene encoding an ADAM or Interactor polypeptide, suspended in a physiologically acceptable carrier or excipient such as saline or phosphate buffered saline, and the like, and then administered to the host. The desired gene product is expressed by the injected cells, which thus introduce the gene product into the host. The introduced gene products can thereby be utilized to treat or ameliorate a disorder (e.g., asthma, obesity, or inflammatory bowel disease) that is related to altered levels of the ADAM or Interactor polypeptide.  
     ANIMAL MODELS  
     [0289] In accordance with the present invention, ADAM or Interactor polynucleotides (e.g., shown in Tables 2-5 and 7, SEQ ID NOs. 1-9, and FIGS.  1 - 12 ) can be used to generate genetically altered non-human animals or human cell lines. Any non-human animal can be used; however typical animals are rodents, such as mice, rats, or guinea pigs. Genetically engineered animals or cell lines can carry a gene that has been altered to contain deletions, substitutions, insertions, or modifications of the polynucleotide sequence (e.g., exon sequence). Such alterations may render the gene nonfunctional, (i.e., a null mutation) producing a “knockout” animal or cell line. In addition, genetically engineered animals can carry one or more exogenous or non-naturally occurring genes, i.e., “transgenes”, that are derived from different organisms (e.g., humans), or produced by synthetic or recombinant methods. Genetically altered animals or cell lines can be used to study ADAM or Interactor gene function, regulation, and treatments for ADAM or Interactor-related diseases. In particular, knockout animals and cell lines can be used to establish animal models and in vitro models for ADAM or Interactor-qter-related illnesses, respectively. In addition, transgenic animals expressing human ADAM or Interactor-qter can be used in drug discovery efforts.  
     [0290] A “transgenic animal” is any animal containing one or more cells bearing genetic information altered or received, directly or indirectly, by deliberate genetic manipulation at a subcellular level, such as by targeted recombination or microinjection or infection with recombinant virus. The term “transgenic animal” is not intended to encompass classical cross-breeding or in vitro fertilization, but rather is meant to encompass animals in which one or more cells are altered by, or receive, a recombinant DNA molecule. This recombinant DNA molecule may be specifically targeted to a defined genetic locus, may be randomly integrated within a chromosome, or it may be extrachromosomally replicating DNA.  
     [0291] Transgenic animals can be selected after treatment of germline cells or zygotes. For example, expression of an exogenous ADAM or Interactor gene or a variant can be achieved by operably linking the gene to a promoter and optionally an enhancer, and then microinjecting the construct into a zygote (see, e.g., Hogan et al.,  Manipulating the Mouse Embryo, A Laboratory Manual,  Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). Such treatments include insertion of the exogenous gene and disrupted homologous genes. Alternatively, the gene(s) of the animals may be disrupted by insertion or deletion mutation of other genetic alterations using conventional techniques (see, e.g., Capecchi, 1989,  Science,  244:1288; Valancuis et al., 1991,  Mol. Cell Biol.,  11:1402; Hasty et al., 1991,  Nature,  350:243; Shinkai et al., 1992,  Cell,  68:855; Mombaerts et al., 1992,  Cell,  68:869; Philpott et al., 1992,  Science,  256:1448; Snouwaert et al., 1992,  Science,  257:1083; Donehower et al., 1992,  Nature,  356:215).  
     [0292] In one aspect of the invention, ADAM or Interactor gene knockout mice can be produced in accordance with well-known methods (see, e.g., M. R. Capecchi, 1989,  Science,  244:1288-1292; P. Li et al., 1995,  Cell  80:401-411; L. A. Galli-Taliadoros et al., 1995,  J. Immunol. Methods  181(1):1-15; C. H. Westphal et al., 1997,  Curr. Biol.  7(7):530-3; S. S. Cheah et al., 2000,  Methods Mol. Biol.  136:455-63). The disclosed murine ADAM or Interactor genomic clone can be used to prepare an ADAM or Interactor targeting construct that can disrupt ADAM or Interactor in the mouse by homologous recombination at the ADAM or Interactor chromosomal locus. The targeting construct can comprise a disrupted or deleted ADAM or Interactor gene sequence that inserts in place of the functioning portion of the native mouse gene. For example, the construct can contain an insertion in the ADAM or Interactor protein-coding region.  
     [0293] Preferably, the targeting construct contains markers for both positive and negative selection. The positive selection marker allows the selective elimination of cells that lack the marker, while the negative selection marker allows the elimination of cells that carry the marker. In particular, the positive selectable marker can be an antibiotic resistance gene, such as the neomycin resistance gene, which can be placed within the coding sequence of an ADAM or Interactor gene to render it non-functional, while at the same time rendering the construct selectable. The herpes simplex virus thymidine kinase (HSV tk) gene is an example of a negative selectable marker that can be used as a second marker to eliminate cells that carry it. Cells with the HSV tk gene are selectively killed in the presence of gangcyclovir. As an example, a positive selection marker can be positioned on a targeting construct within the region of the construct that integrates at the locus of the ADAM or Interactor gene. The negative selection marker can be positioned on the targeting construct outside the region that integrates at the locus of the ADAM or Interactor gene. Thus, if the entire construct is present in the cell, both positive and negative selection markers will be present. If the construct has integrated into the genome, the positive selection marker will be present, but the negative selection marker will be lost.  
     [0294] The targeting construct can be employed, for example, in embryonal stem cell (ES). ES cells may be obtained from pre-implantation embryos cultured in vitro (M. J. Evans et al., 1981,  Nature  292:154-156; M. O. Bradley et al., 1984,  Nature  309:255-258; Gossler et al., 1986,  Proc. Natl. Acad. Sci. USA  83:9065-9069; Robertson et al., 1986,  Nature  322:445-448; S. A. Wood et al., 1993,  Proc. Natl. Acad. Sci. USA  90:4582-4584). Targeting constructs can be efficiently introduced into the ES cells by standard techniques such as DNA transfection or by retrovirus-mediated transduction. Following this, the transformed ES cells can be combined with blastocysts from a non-human animal. The introduced ES cells colonize the embryo and contribute to the germ line of the resulting chimeric animal (R. Jaenisch, 1988,  Science  240:1468-1474). The use of gene-targeted ES cells in the generation of gene-targeted transgenic mice has been previously described (Thomas et al., 1987,  Cell  51:503-512) and is reviewed elsewhere (Frohman et al., 1989,  Cell  56:145-147; Capecchi, 1989,  Trends in Genet.  5:70-76; Baribault et al., 1989,  Mol. Biol. Med.  6:481-492; Wagner, 1990,  EMBO J.  9:3025-3032; Bradley et al., 1992,  Bio/Technology  10: 534-539).  
     [0295] Several methods can be used to select homologously recombined murine ES cells. One method employs PCR to screen pools of transformant cells for homologous insertion, followed by screening individual clones (Kim et al., 1988,  Nucleic Acids Res.  16:8887-8903; Kim et al., 1991,  Gene  103:227-233). Another method employs a marker gene is constructed which will only be active if homologous insertion occurs, allowing these recombinants to be selected directly (Sedivy et al., 1989,  Proc. Natl. Acad. Sci. USA  86:227-231). For example, the positive-negative selection (PNS) method can be used as described above (see, e.g., Mansour et al., 1988,  Nature  336:348-352; Capecchi, 1989,  Science  244:1288-1292; Capecchi, 1989,  Trends in Genet.  5:70-76). In particular, the PNS method is useful for targeting genes that are expressed at low levels.  
     [0296] The absence of functional ADAM or Interactor genes in the knockout mice can be confirmed, for example, by RNA analysis, protein expression analysis, and functional studies. For RNA analysis, RNA samples are prepared from different organs of the knockout mice and the ADAM or Interactor transcript is detected in Northern blots using oligonucleotide probes specific for the transcript. For protein expression detection, antibodies that are specific for the ADAM or Interactor polypeptide are used, for example, in flow cytometric analysis, immunohistochemical staining, and activity assays. Alternatively, functional assays are performed using preparations of different cell types collected from the knockout mice.  
     [0297] Several approaches can be used to produce transgenic mice. In one approach, a targeting vector is integrated into ES cell by homologous recombination, an intrachromosomal recombination event is used to eliminate the selectable markers, and only the transgene is left behind (A. L. Joyner et al., 1989,  Nature  338(6211):153-6; P. Hasty et al., 1991,  Nature  350(6315):243-6; V. Valancius and O. Smithies, 1991,  Mol. Cell Biol.  11(3):1402-8; S. Fiering et al., 1993,  Proc. Natl. Acad. Sci. USA  90(18):8469-73). In an alternative approach, two or more strains are created; one strain contains the gene knocked-out by homologous recombination, while one or more strains contain transgenes. The knockout strain is crossed with the transgenic strain to produce new line of animals in which the original wild-type allele has been replaced (although not at the same site) with a transgene. Notably, knockout and transgenic animals can be produced by commercial facilities (e.g., The Lerner Research Institute, Cleveland, OH; B&amp;K Universal, Inc., Fremont, Calif.; DNX Transgenic Sciences, Cranbury, N.J.; Incyte Genomics, Inc., St. Louis, Mo.).  
     [0298] Transgenic animals (e.g., mice) containing a nucleic acid molecule which encodes a human ADAM or Interactor polypeptide, may be used as in vivo models to study the overexpression of an ADAM or Interactor gene. Such animals can also be used in drug evaluation and discovery efforts to find compounds effective to inhibit or modulate the activity of a 12q23-qter gene, such as for example compounds for treating respiratory disorders, diseases, or conditions. One having ordinary skill in the art can use standard techniques to produce transgenic animals which produce a human ADAM or Interactor polypeptide, and use the animals in drug evaluation and discovery projects (see, e.g., U.S. Pat. No. 4,873,191 to Wagner; U.S. Pat. No. 4,736,866 to Leder).  
     [0299] In another embodiment of the present invention, the transgenic animal can comprise a recombinant expression vector in which the nucleotide sequence that encodes a human ADAM or Interactor polypeptide is operably linked to a tissue specific promoter whereby the coding sequence is only expressed in that specific tissue. For example, the tissue specific promoter can be a mammary cell specific promoter and the recombinant protein so expressed is recovered from the animal&#39;s milk.  
     [0300] In yet another embodiment of the present invention, an ADAM or Interactor gene “knockout” can be produced by administering to the animal antibodies (e.g., neutralizing antibodies) that specifically recognize an endogenous ADAM or Interactor polypeptides. The antibodies can act to disrupt function of the endogenous ADAM or Interactor polypeptide, and thereby produce a null phenotype. In one specific example, an orthologous mouse ADAM or Interactor polypeptide or peptide can be used to generate antibodies. These antibodies can be given to a mouse to knockout the function of the mouse ADAM or Interactor ortholog.  
     [0301] In another embodiment of the present invention, non-mammalian organisms may be used to study ADAM or Interactor genes and ADAM or Interactor-related diseases. In particular, model organisms such as  C. elegans, D. melanogaster,  and  S. cerevisiae  may be used. Orthologs of ADAM or Interactor genes can be identified in these model organisms, and mutated or deleted to produce strains deficient for ADAM or Interactor genes. Human ADAM or Interactor genes can then be tested for the ability to “complement” the deficient strains. Such strains can also be used for drug screening. The ADAM or Interactor orthologs can be used to facilitate the understanding of the biological function of the human ADAM or Interactor genes, and assist in the identification of binding factors (e.g., agonists, antagonists, and inhibitors).  
     EXAMPLES  
     [0302] The examples as set forth herein are meant to exemplify the various aspects of the present invention and are not intended to limit the invention in any way.  
     Example 1  
     [0303] Family Collection  
     [0304] Asthma is a complex disorder that is influenced by a variety of factors, including both genetic and environmental effects. Complex disorders are typically caused by multiple interacting genes, some contributing to disease development and some conferring a protective effect. The success of linkage analyses in identifying chromosomes with significant LOD scores is achieved in part as a result of an experimental design tailored to the detection of susceptibility genes in complex diseases, even in the presence of epistasis and genetic heterogeneity. Also important are rigorous efforts in ascertaining asthmatic families that meet strict guidelines, and collecting accurate clinical information.  
     [0305] Given the complex nature of the asthma phenotype, non-parametric affected sib pair analyses were used to analyze the genetic data. This approach does not require parameter specifications such as mode of inheritance, disease allele frequency, penetrance of the disorder, or phenocopy rates. Instead, it determines whether the inheritance pattern of a chromosomal region is consistent with random segregation. If it is not, affected siblings inherit identical copies of alleles more often than expected by chance. Because no models for inheritance are assumed, allele-sharing methods tend to be more robust than parametric methods when analyzing complex disorders. They do, however, require larger sample sizes to reach statistically significant results.  
     [0306] At the outset of the program, the goal was to collect 400 affected sib-pair families for the linkage analyses. Based on a genome scan with markers spaced ˜10 cM apart, this number of families was predicted to provide &gt;95% power to detect an asthma susceptibility gene that caused an increased risk to first-degree relatives of 3-fold or greater. The assumed relative risk of 3-fold was consistent with epidemiological studies in the literature that suggest an increased risk ranging from 3- to 7-fold. The relative risk was based on gender, different classifications of the asthma phenotype (i.e., bronchial hyper-responsiveness versus physician&#39;s diagnosis) and, in the case of offspring, whether one or both parents were asthmatic.  
     [0307] The family collection efforts exceeded the initial goal of 400, and resulted in a total of 444 affected sibling pair (ASP) families, with 342 families from the UK and 102 families from the US. The ASP families in the US collection were Caucasian with a minimum of two affected siblings that were identified through both private practice and community physicians as well as through advertising. A total of 102 families were collected in Kansas, Nebraska, and Southern California. In the UK collection, Caucasian families with a minimum of two affected siblings were identified through physicians&#39; registers in a region surrounding Southampton and including the Isle of Wight. In both the US and UK collections, additional affected and unaffected sibs were collected whenever possible.  
     [0308] An additional 63 families from the United Kingdom were utilized from an earlier collection effort with different ascertainment criteria. These families were recruited either: 1) without reference to asthma and atopy; or 2) by having at least one family member or at least two family members affected with asthma. The randomly ascertained samples were identified from general practitioner registers in the Southampton area. For families with affected members, the probands were recruited from hospital based clinics in Southampton. Seven pedigrees extended beyond a single nuclear family. The phenotypic and genotypic data information for 17 markers for 21 of these 63 families was obtained from the website http://cedar.genetics.soton.ac.uk/pub/PROGRAMS/BETA/data/bet12.ped.  
     [0309] Families were included in the study if they met all of the following criteria: 1) the biological mother and biological father were Caucasian and agreed to participate in the study; 2) at least two biological siblings were alive, each with a current physician diagnosis of asthma, and were 5 to 21 years of age; and 3) the two siblings were currently taking asthma medications on a regular basis. This included regular, intermittent use of inhaled or oral bronchodilators and regular use of cromolyn, theophylline, or steroids.  
     [0310] Families were excluded from the study if they met any one of the following criteria: 1) both parents were affected (i.e., with a current diagnosis of asthma, having asthma symptoms, or on asthma medications at the time of the study); 2) any of the siblings to be included in the study was less than 5 years of age; 3) any asthmatic family member to be included in the study was taking beta-blockers at the time of the study, 4) any family member to be included in the study had congenital or acquired pulmonary disease at birth (e.g., cystic fibrosis), a history of serious cardiac disease (myocardial infarction), or any history of serious pulmonary disease (e.g., emphysema); or 5) any family member to be included in the study was pregnant.  
     [0311] An extensive clinical instrument was designed and data from all participating family members were collected. The case report form (CRF) included questions on demographics, medical history including medications, a health survey on the incidence and frequency of asthma, wheeze, eczema, hay fever, nasal problems, smoking, and questions on home environment. Data from a video questionnaire designed to show various examples of wheeze and asthmatic attacks were also included in the CRF. Clinical data, including skin prick tests to 8 common allergens, total and specific IgE levels, and bronchial hyper-responsiveness following a methacholine challenge, were also collected from all participating family members. All data were entered into a SAS dataset by IMTCI, a CRO; either by double data entry or scanning followed by on-screen visual validation. An extensive automated review of the data was performed on a routine basis and a full audit at the conclusion of the data entry was completed to verify the accuracy of the dataset.  
     Example 2  
     [0312] Genome Scan  
     [0313] In order to identify chromosomal regions linked to asthma, the inheritance pattern of alleles from genetic markers spanning the genome was assessed on the collected family resources. As described above, combining these results with the segregation of the asthma phenotype in these families allows the identification of genetic markers that are tightly linked to asthma. In turn, this provides an indication of the location of genes predisposing affected individuals to asthma. The genotyping strategy was twofold: 1) to conduct a genome wide scan using markers spaced at approximately 10 cM intervals; and 2) to target ten chromosomal regions for high density genetic mapping. The initial candidate regions for high-density mapping were chosen based on suggestions of linkage to these regions by other investigators.  
     [0314] Genotypes of PCR amplified simple sequence microsatellite genetic linkage markers were determined using ABI model 377 Automated Sequencers (PE Applied Biosystems). Microsatellite markers were obtained from Research Genetics Inc. (Huntsville, Ala.) in the fluorescent dye-conjugated form (see Dubovsky et al., 1995,  Hum. Mol. Genet.  4(3):449-452). The markers comprised a variation of a human linkage mapping panel as released from the Cooperative Human Linkage Center (CHLC), also known as the Weber lab screening set version 8. The variation of the Weber 8 screening set consisted of 529 markers with an average spacing of 6.9 cM (autosomes only) and 7.0 cM (all chromosomes). Eighty-nine percent of the markers consisted of either tri- or tetra-nucleotide microsatellites. There were no gaps present in chromosomal coverage greater than 17.5 cM.  
     [0315] Study subject genomic DNA (5 μl; 4.5 ng/μl) was amplified in a 10 μl PCR reaction using AmpliTaq Gold DNA polymerase (0.225 U); 1× PCR buffer (80 mM (NH 4 ) 2 SO 4 ; 30 mM Tris-HCl (pH 8.8); 0.5% Tween-20); 200 μM each dATP, dCTP, dGTP and dTTP; 1.5-3.5 μM MgCl 2 ; and 250 μM forward and reverse PCR primers. PCR reactions were set up in 192 well plates (Costar) using a Tecan Genesis 150 robotic workstation equipped with a refrigerated deck. PCR reactions were overlaid with 20 μl mineral oil, and thermocycled on an MJ Research Tetrad DNA Engine equipped with four 192 well heads using the following conditions: 92° C. for 3 min; 6 cycles of 92° C. for 30 sec, 56° C. for 1 min, 72° C. for 45 sec; followed by 20 cycles of 92° C. for 30 sec, 55° C. for 1 min, 72° C. for 45 sec; and a 6 min incubation at 72° C.  
     [0316] PCR products of 8-12 microsatellite markers were subsequently pooled into two 96-well microtitre plates (2.0 μl PCR product from TET and FAM labeled markers, 3.0 μl HEX labeled markers) using a Tecan Genesis 200 robotic workstation and brought to a final volume of 25 μl with H 2 O. Following this, 1.9 μl of pooled PCR product was transferred to a loading plate and combined with 3.0 μl loading buffer (2.5 μl formamide/blue dextran (9.0 mg/ml), 0.5 μl GS-500 TAMRA labeled size standard, ABI). Samples were denatured in the loading plate for 4 min at 95° C., placed on ice for 2 min, and electrophoresed on a 5% denaturing polyacrylamide gel (FMC on the ABI 377XL). Samples (0.8 μl) were loaded onto the gel using an 8 channel Hamilton Syringe pipettor.  
     [0317] Each gel consisted of 62 study subjects and 2 control subjects (CEPH parents ID #1331-01 and 1331-02, Coriell Cell Repository, Camden, N.J.). Genotyping gels were scored in duplicate by investigators blind to patient identity and affection status using GENOTYPER analysis software V 1.1.12 (ABI; PE Applied Biosystems). Nuclear families were loaded onto the gel with the parents flanking the siblings to facilitate error detection. The final tables obtained from the GENOTYPER output for each gel analysed were imported into a SYBASE Database.  
     [0318] Allele calling (binning) was performed using the SYBASE version of the ABAS software (Ghosh et al., 1997,  Genome Research  7:165-178). Offsize bins were checked manually and incorrect calls were corrected or blanked. The binned alleles were then imported into the program MENDEL (Lange et al., 1988,  Genetic Epidemiology,  5:471) for inheritance checking using the USERM13 subroutine (Boehnke et al., 1991,  Am. J. Hum. Genet.  48:22-25). Non-inheritance was investigated by examining the genotyping traces and, once all discrepancies were resolved, the subroutine USERM13 was used to estimate allele frequencies.  
     Example 3  
     [0319] Linkage Analysis  
     [0320] Chromosomal regions harboring asthma susceptibility genes were identified by linkage analysis of genotyping data and three separate phenotypes, asthma, bronchial hyper-responsiveness, and atopic status.  
     [0321] 1. Asthma Phenotype: For the initial linkage analysis, the phenotype and asthma affection status were defined by a patient who answered the following questions in the affirmative: i) Have you ever had asthma? ii) Do you have a current physician&#39;s diagnosis of asthma? and iii) Are you currently taking asthma medications? Medications included inhaled or oral bronchodilators, cromolyn, theophylline, or steroids. Multipoint linkage analyses of allele sharing in affected individuals were performed using the MAPMAKER/SIBS analysis program (L. Kruglyak and E. S. Lander, 1995,  Am. J. Hum. Genet.  57:439-454).  
     [0322] 2. Phenotypic Subgroups: Nuclear families were ascertained by the presence of at least two affected siblings with a current physician&#39;s diagnosis of asthma, as well as the use of asthma medication. In the initial analysis (see above), the evidence was examined for linkage based on that dichotomous phenotype (asthma—yes/no). To further characterize the linkage signals, additional quantitative traits were measured in the clinical protocol. Since quantitative trait loci (QTL) analysis tools with correction for ascertainment were not available, the following approach was taken to refine the linkage and association analyses:  
     [0323] i. Phenotypic subgroups that could be indicative of an underlying genotypic heterogeneity were identified. Asthma subgroups were defined according to 1) bronchial hyper-responsiveness (BHR) to methacholine challenge; or 2) atopic status using quantitative measures like total serum IgE and specific IgE to common allergens.  
     [0324] ii. Non-parametric linkage analyses were performed on subgroups to test for the presence of a more homogeneous sub-sample. If genetic heterogeneity was present in the sample, the amount of allele sharing among phenotypically similar siblings was expected to increase in the appropriate subgroup in comparison to the full sample. A narrower region of significant increased allele sharing was also expected to result unless the overall LOD score decreased as a consequence of having a smaller sample size and of using an approximate partitioning of the data.  
     [0325] 3. Results for BHR and IqE: PC 20 , the concentration of methacholine resulting in a 20% drop in FEV 1  (forced expiratory volume), was polychotomized into four groups and analyses were performed on the subsets of asthmatic children with borderline to severe BHR (PC 20 ≦16 mg/ml) or PC 20 (16). Total IgE was dichotomized using an age specific cutoff for elevated levels (one standard deviation above the mean: 52 kU/L for age 5-9; 63 kU/L for age 10-14; 75 kU/L for age 15-18; and 81 kU/L for adults). Similarly, a dichotomous variable was created using specific IgE to common allergens. An individual was assigned a high specific IgE value if his/her level was positive (grass or tree) or elevated (&gt;0.35 KU/L for cat, dog, mite A, mite B, alternaria, or ragweed) for at least one such measure.  
     [0326] Based on the identification of an ADAM33 (Gene 216) located within chromosome 20 as described in U.S. patent application Ser. No. 09/834,597 and PCT/US01/12245 other family members, substrates and interactors were investigated as additional candidate genes (“disorder associated genes”). A pattern of evidence by linkage analysis pointed to the existence of several asthma susceptibility loci within the chromosomal regions identified in Table 1. This was supported by the initial analysis of the asthma (yes/no) phenotype with further localization by analyses of BHR, total IgE, and specific IgE in asthmatic individuals. Table 1 describes multipoint analysis results across the four phenotypes described above. The first column contains the gene name and the second column contains the chromosome number. The location of the gene is denoted in column three in centemorgans. The corresponding phenotypes and respective LOD scores are contained within the fourth, fifth, sixth and seventh columns. The results thus indicate that the genes located within these regions having a significant LOD score are involved in asthma and related diseases thereof.  
                                           TABLE 1                                               Asthma &amp;   Asthma &amp;   Asthma &amp;           Chr.   Loc. (cM)   Asthma   BHR   Total IgE   Specific IgE                                                                ADAMI9   5   159.8   1.11   1.33   0.95   1.67       NRG2   5   142.9   0.78   1.49   0.70   0.69       NRG1   8   61.6   1.04   1.09   1.08   0.64       SH3GL2.EN   9   18.0   0.94   2.99   1.00   1.22       DOPHILIN1       SH3GL1.EN   19   15.6   2.86   2.30   2.22   2.66       DOPHILIN2       ADAM3A   8   34.8-64.6   0.85   0.59   1.21   0.47       ADAM7   8   48.1   0.94   0.47   1.30   0.40       ADAM28   8   47.8   0.94   0.48   1.30   0.41       ADAM9   8   60.0-65.8   1.10   1.14   1.00   0.70       ADAM2   8   64.6   1.19   1.22   0.89   0.79       ADAM18   8   64.6   1.19   1.22   0.89   0.79       ADAMTS2   5   192.8   1.13   0.71   1.68   2.51       ADAMTS3   4   80.9   0.77   0.71   1.48   0.31       ADAMTS9   3   89.9   0.26   0.29   1.23   0.23       ADAMDEC1   8   47.9   0.94   0.48   1.30   0.40                  
 
     Example 4  
     [0327] Gene Identification  
     [0328] Based on the linkage results above, genes were identified at the chromosomal locations described of Table 1 using the National Council for Biotechnology website (www.ncbi.gov). The genes and their related information are contained within Table 2. In addition, the alternate splice variants are also provided in Table 2. Column one, two and three of Table 2 contain the gene identifier, gene symbol and gene name, respectively. The accession numbers for the corresponding cDNA sequence are contained in the fourth column. The amino acid sequence accession number is listed in the fifth column. The genomic sequences accession numbers are provided in the sixth and seventh columns. In particular, the genomic contig for the region containing the gene is provided in the sixth column. The individual bacterial artificial chromosomes spanning the region containing the gene are listed with their respective accession numbers in seventh column. One skilled in the art could obtain the above described nucleic and amino acid sequences using the accession numbers provided herein. The eighth column provides the genetic marker of the location on the chromosome. And the gene description is provided in the ninth column.  
     [0329] Based on the linkage analysis, the genes described in Table 2 are involved in asthma and related diseases thereof.  
                                               TABLE 2                                           GenBank                                   GenBank   Genomic                   GenBank NT   Protein   Contig   GenBank       Gene Name   Gene Symbol   Gene Name   Accession #   Accession #   Accession #   Genomic Clone Accession #   Marker   Description                  Gene845   Adam19   a disintegrin and metalloproteinase   NM_023038   NP_075525   NT_006788   AC008676, AC008694   stSG53531   This variant (isoform-1) encodes a               domain 19 (meltrin beta)                       longer isoform which is divergent from                                       isoform 2 in the C-terminus.       Gene845   Adam19   a disintegrin and metalloproteinase   NM_033274   NP_50377   NT_006788   AC008676, AC008694   s1SG53531   This variant (isoform-2) encodes a               domain 19 (mellna beta)                       shorter sotorm which is divergent from                                       isoform 1 in the C-terminus       Gene847   NRG2   neuregulin 2   NM_004883   NP_004874   NT_007018   AC008667, AC008523, AC011589,       Splice vanant 1 lacks enons 6 and 7                               AC010292, AC026272, AC011379       Gene847   NRG2   neuregulin 2   NM_013981   NP_053584   NT_007018   AC008667, AC008523, AC011589,       Splice variant 2 lacks exons 5 and 7                               AC010292, AC028272, AC011379       Gene847   NRG2   neuregulin 2   NM_013982   NP_053585   NT_007018   AC008667, AC008523, ACO11589,       Splice variant 3 encludes enon 6                               AC010292, AC026272, AC011379       Gene847   NRG2   neuregulin 2   NM_013983   NP_053586   NT_007018   AC008667, AC008523, AC011589,       Splice variant 4 excludes exon 5                               AC010292, AC026272, AC011379       Gene847   NRG2   neuregulin 2   NM_013984   NP_053587   NT_007018   AC008667, AC008523, AC011589,       Splice variant 5 excludes enons 7, 9-12                               AC010292, AC026272, AC011379       and its enon 8 is missing 70 bps at the 3                                       end. The protein product does not have                                       transmembrane and cytoplasmic tail                                       regions       Gene847   NRG2   neuregulin 2   NM_013985   NP_053588   NT_007018   AC008667, AC008523, AC011589,       Splice variant 6 excludes exons 8-12                               AC010292, AC026272, AC011379       and its exon 7 is missing 3 bps at the 3                                       end. The protein product does not have                                       tranumembrane and cytoplasmic tail                                       regions       Gene891   NRG1   neuregulin 1   NM_004495   NP_004486   NT_007995   AC083977, AC013561, AC128834,   stSG4083,    This variant (HRG-gamma) has a longer                               AF181895   SHGC-12780,   5&#39; UTR and longer 3&#39; UTR than vanant                                   WI-18803   HRG-alpha The CDS is truncated on                                       the 3&#39; end by 1289 bps resulhng in a                                       protein product equivalent to the N-                                       terminal 211 amino acids of the HRG-                                       alpha isoform.       Gene891   NRG1   neuregulin 1   NM_013956   NP_039250   NT_007995   AC083977, AC013561, AF128834,   stSG4083,   This vanant(HRG-betal), along with                               AF181895   SHGC-12780,   HRG-alpha, beta2, and beta3 vananits,                                   WI-18803   was idenrified in nartous normal tissues                                       and cancer cell lines The protein                                       product encoded by this vadant is                                       distinct from that of HRG-alpha in the                                       region of amino acids 213-239       Gene891   NRG1   neuregulin 1   NM_013957   NP_039251   NT_007995   AC083977, AC013561, AF128834,   stSG4083,   This vadant (HRG-beta2), along with                               AF181895   SHGC-12780,   HRG-alpha, beta1, and beta3 variants,                                   WI-18803   was identified in various normal issues                                       and cancer cell lines. The protein                                       product encoded by this variant is                                       distinct from that of HRG-alpha at the                                       region of amino acids 213-231.       Gene891   NRG1   neuregulin 1   NM_013958   NP_039252   NT_007995   AC083977, AC013561, AF128834,   stSG4083,   This variant (HRG-beta3), along with                               AF181895   SHGC-12780,   HRG-alpha, beta1 and beta2 variants,                                   WI-18803   was identified in various normal tissues                                       and cancer cell lines. The protein                                       product encoded by this variant is 399                                       amino acid shorter than, but the first N-                                       terminal 212 amino acids is the same                                       as, that of HRG-alpha       Gene891   NRG1   neuregulin 1   NM_013959   NP_039253   NT_007995   AC083977, AC013561, AF128834,   stSG4083,   This vanant (SMDF) is expressed mainly                               AF181895   SHGC-12780,   in the nervous system. It contains a C-                                   WI-18803   terminal EGF-like domain and a unique                                       N-terminal sequence which lacks an Ig-                                       like domain and is distinct from all                                       known HRG-variants       Gene891   NRG1   neuregulin 1   NM_013980   NP_039254   NT_007995   AC083977, AC013561, AF128834,   stSG4083,   This variant (ndf43) in one of the HRG-                               AF181895   SHGC-12780,   variants It has shorter 5 UTR, shorter                                   WI-18803   CDS, and longer 3&#39; UTR than the variant                                       HRG-alpha Its amino acid sequence is                                       178 amino acid shorter than, and the                                       last C-terminal 38 amino acids differs                                       from, that of the variant HRG-alpha.       Gene891   NRG1   neuregulin 1   NM_013961   NP_039255   NT_007995   AC083977, AC013561, AF128834,   s1SG4083,   The GGF (also called GGFHFB1)                               AF161895   ShIGC-12780,   variant is identical to HRG-beta3 variant,                                   WI-18603   except for its shorter 5&#39; and 3&#39; UTRs.                                       The GGF and GGF2 vanants are                                       expressed in the nervous system and                                       function as a neuronal signal that                                       promotes the proliferation and survival                                       of the oligodendrocyte and the                                       myelinating cells.       Gene891   NRG1   neuregulin 1   NM_013962   NP_039256   NT_007995   AC083977, AC013561, AF126834,   s1SG4083,   The GGF2 (also called GGFHBS5)                               AF181895   SHGC-12760,   variant differs from GGF variant at N-                                   WI-18803   terminal coding segments designated 1                                       or 2, and their 5&#39; UTR ate unrelated                                       Botrivadants are expressed in the                                       nervous system and function as a                                       neuronal signal that promotes the                                       proliferation and survival of the                                       oligodendrocyte and the myalinating                                                                           cell       Gene891   NRG1   neuregulin 1   NM_013964   NP_039258   NT_007995   AC083977, AC013561, AF128634,   stSG4083,   This variant (HRG-alpha), along with                               AF181895   SHGC-12780,   HRG-betal, beta2, and beta3 variants,                                   WI-18603   was identified in vanous normal tissues                                       and cancer cell lines. The protein                                       product encoded by this variant is                                       distinct from those of HRG-beta vanants                                       at the region of amino acids 213-234.       Gene874   SH3GL2   SH3-domain GRB2-like 2   NM_003026   NL_003017   NT_029370   AL139115       SH3-domain GRB2-like 2           (Endophilin1)       Gene803   SH3GL1   SH3-domain GRB2-like 1   NM_003025   NP_003016   NT_011245   AF190465, AC007292       SH3-domain GRB2-like 1 This vanant           (Endophilin2)                           (1) has longer exons E and F as                                       compared to vanant 2. There are 369                                       amino acids.       Gene803   SH3GL1   SH3-domain GRB2-like 1   AK097616   N/A   NT_011245   AF190465, AC007292       SH3-domain GRB2-like 1 This variant           (Enxophilin2)                           (2) has shorter exons E and F as                                       compared to vanant 1. This variant is 64                                       amino acids shorter than vanant 1       Gene894   ADAM3A   a disintegrin and metalloproteinase   X89657       no alignment           a disintegrin and metalloproteinase               domain 3a (cyntestin 1)           in Draft           domain 3a (cyntestin 1) pseudogene                           sequence       Gene895   ADAM28   a disintegrin and metalloproteinase   NM_014265   NP_055080   NT_008130   AC023202, AC044891   stSG42867   This variant (1) encodes isoform 1,               domain 28                       which has the same amino acid length                                       as isoform 2 encoded by variant 2                                       These two isoforms differ from each                                       other in the next to last amino acid. In                                       addition, variant 1 contains a 272 bps                                       longer 3&#39; UTR than variant 2.       Gene895   ADAM28   a disintegrin and metalloproteinase   NM_021777   NP_068547   NT_008130   AC023202, AC044891   s1tG42867   This variant (3) contains a shorter 3&#39;               domain 28                       coding region and a different 3&#39; UTR                                       from variant 2. The isoform 3 encoded                                       by this variant lacks transmembrane and                                       cytoplasmic domains, as compared to                                       isoform 2 encoded by variant 2       Gene895   ADAM28   a disintegrin and metatoproleinase   NM_021778   NP_068548   NT_008130   AC023202, AC044891   stSG42867   This variant (2) contains a longer 3&#39;               domain 28                       coding region and different 3&#39; UTR from                                       vacant 3 The isoform 2 encoded by this                                       variant contains transmembrane and                                       cytoplasmic domains, as compared to                                       isoform 3 encoded by variant 3.       Gene895   ADAM7   a disintegrin and metalloproteinase   AF215824   AAG43987   NT_023666   AC024958, AC018422       a disintegrin and metalloprotenase               domain 7                       domain 7       Gene897   ADAM9   a disintegrin and metalloproteinase   NM_003816   NP_003807   no alignment       D14665,   a disintegris and metalloproteinase               domain 9 (meltrin gamma)           is Draft           domain 9 preproprotein                           sequence       RH25259       Gene898   ADAM2   a disintegrin and metalloproteinase   NM_001464   NP_001455   NT_008045   AF178650, AC018807   U52370   a disintegrin and metalloproteinase               domain 2 (fertilin beta)                       domain 2 proprotein       Gene899   ADAM18   a disintegrin and melalloproteinase   NM_014237   NP_055052   NT_008045   AF178650, AC018807       a disintegrin and metalloproteinase               domain 18                       domain 18 preproprotein       Gene962   ADAMTS2   a disinlegrin-like and   NM_014244   NP_055059   NT_006802   AC010216, AC008470, AC008544,       This variant (1) and variant 2 share               metalloprolease (reprolysin type)               AC034202, AC023587, AC016557       identical 5&#39;-region of 1629 bps, which               with thrombospondin                       encodes N-terminal 543 amino acids,               type 1 motif, 2                       but they have diverse 3-region Vanant                                       1 is 1935 bps longer than variant 2 in                                       the 3-region, and the isoform 1 encoded                                       by variant 1 is 645 amino acids longer                                       than isoform 2 encoded by variant 2.                                       Isoform 1 contains 4 C-terminal TS                                       motifs, whereas isoform 2 lacks C-                                       terminal TS mofits.       Gene962   ADAMTS2   a disintegrin-like and   NM_021599   NP_067610   NT_006802   AC010216,       This variant (2) and variant 1 share               melalloprotease (reprolysin type)               AC008470,       identical 5&#39;-region of 1629 bps, which               with thrombospondin               AC008544,       encodes N-terminal 543 amino acids,               type 1 motif, 2               AC034202,       but they have diverse 3-region Vanant                               AC023587,       is 1935 bps shorter than variant 1 in                               AC0165572       the 3-region, and the isoform 2 encoded                                       by variant 2 is 645 amino acids shorter                                       than isoform 1 encoded by variant 1                                       Isoform 2 lacks C-terminal TS motifs,                                       whereas isoform 1 contains 4 C-terminal                                       TS motifs Variant 2 is resulted from                                       retention of a portion of an intron and                                       the use of a polyA signal which is                                       located within the intron sequence.       Gene901   ADAMTS3   a disintegrin-like and   XM_036683   XP_036683   NT_022833   AC011819,   A009A40,   a disintegrin-like and melalloprotease               metalloprotease (reprolysin type)               AC055844,   stSG39575,   (reprolysin type) with thrombospondin               with thrombospondin               AC022843,   SHGC-50515   type 1 motif, 3               type 1 motif, 3               AC088203       Gene902   ADAMTS9   a disintegrin-like and   NM_020249   NP_084834   no alignment           a disintegrin and metalloproteinase with               metalloprolease (reprolysin type)           in Draft           thrombospondin motifs-9 preproprotein               with thrombospondin           sequence               type 1 motif, 9       Gene903   ADAMDEC1   ADAM-like, decysin 1   NM_014479   NP_055294   NT_023666   AC024958       ADAM-like, decysin 1 a disintegrin                                       protease                  
 
     Example 5  
     [0330] Mutation Analysis  
     [0331] Gene 803, Gene 845, Gene 847, Gene 874 and Gene 962 disorder-associated candidate genes were identified using the above procedures, and exons from these genes were subjected to mutation detection analysis. A combination of fluorescent single stranded confirmation (SSCP) analysis (ABI), DNA sequencing, and other sequence analysis methods described herein were utilized to precisely identify and determine nucleotide sequence variants. SSCP analysis was used to screen individual DNA sequences for variants. Briefly, PCR was used to generate templates from unrelated asthmatic individuals. Non-asthmatic individuals were used as controls. Enzymatic amplification of the disorder-associated genes was accomplished using primers flanking each exon and the putative 5′ regulatory elements of each gene. The primers were designed to amplify each exon, as well as 15 or more base pairs of each intron on either side of the splice site. The forward and the reverse primers had two different dye colors to allow analysis of each strand, and independent confirmation of variants. PCR reactions were optimized for each exon primer pair. Buffer and cycling conditions were specific to each primer set. PCR products were denatured using a formamide dye, and electrophoresed on non-denaturing acrylamide gels with varying concentrations of glycerol (at least two different glycerol concentrations).  
     [0332] Primers utilized in fluorescent SSCP experiments to screen coding and non-coding regions of Gene 803, Gene 845, Gene 847, Gene 874 and Gene 962 for polymorphisms are provided in Table 3. The first column list the genes targeted for mutation analysis. The second column list the specific exons analyzed. The assigned primer names are described in the third column. The fourth and fifth columns list the forward primer sequences and the reverse primer sequences, respectively. The genes listed in the first column of Table 3 correspond to the gene identifiers in the first column of Table 2.  
               TABLE 3                          SSCP PRIMERS                                 Gene   Exon   SSCP Assay   Forward Sequence   Reverse Sequence               845   B   1792_845_B_F_1793_845_B_R   GGAGCGTCTCGACAGAGG   AAGGCTACTCCCAGGTCTCC               845   C   1794_845_C_F_1795_845_C_R   CTGGGATTCCAATGGTTTTG   AGAGTGGGCCAGAAACAGAA               845   D   1796_845_D_F_1797_845_D_R   TCCTGTGGATCAATGTTGGA   CTTCCTTCCAGAACAGCGAC               845   E   1798_845_E_F_1799_845_E_R   GTTGTTGCTAGGAGGGTGGA   TCCCTTCAGAGGAGAGACCA               845   F   1800_845_F_F_1801_845_F_R   CATCCATGACCATCCTGAGA   TTGAAACTTCCATTCCTGGG               845   G   1802_845_G_F_1803_845_G_R   CTAAGACCTACACAAGGGACTTTT   CAGGTTGATTTCTGCACTGAG               845   H   1804_845_H_F_1805_845_H_R   CGGAGGTAGCTGCTGCTTAT   AACATTTCCCCAAAGCAGTCT               845   I   1806_845_I_F_1807_845_I_R   CAAGACAAGTAATGGGGCG   GGCACCTTTCCCACAAGTA               845   J   1808_845_J_F_1809_845_J_R   ATCCCAGGTGGTATTGACAGA   CAGCCAAGGACAACACAACA               845   K   1810_845_K_F_1811_845_K_R   CCACTTACTCCCAGGCACAT   CTGGTCTTGAAAGGCAGCTC               845   L   1842_845_L_F_1813_845_L_R   GTCCCCTTGACCTTGACCTC   AACCCCTGGGTCACACTGTC               845   M   1814_845_M_F_1815_845_M_R   AGGAGTGACAGCACGAGTGA   CAAATTCTTCCCCTCCCACT               845   N   1816_845_N_F_1817_845_N_R   TTGCTAGAGAGCTGGGGTTC   AGTCCTGTGGTCCCACTGTC               845   O   1818_845_O_F_1819_845_O_R   TGGGGAGGAGATTGACTGTG   CAAAACTACCCTGAGGGCCA               845   P   1820_845_P_F_1821_845_P_R   GGGGCTTCTGACAGATGAGT   AGTTGGGCAACAGTGAGGAC               845   Q   1822_845_Q_F_1823_845_Q_R   GACTGAAGCTCTCTGGTGCC   CTCCTCAGGACCTCGGTAGA               845   Q   1824_845_Q_F_1825_845_Q_R   TGCCCATTGACACCACTATC   CATCCTTCCCTCAGACCTCA               845   R   1826_845_R_F_1827_845_R_R   TCTTGCCTCCTAACTCCCAA   GACCTGGAGCAAAGAAAGGG               845   S   1828_845_S_F_1829_845_S_R   CTGGGTTCTGGCTTCTCTGT   CTCACAAAAGCGGGCAGT               845   T   1830_845_T_F_1831_845_T_R   AAATCTGCTGTAGCCGAGACA   TGGAGACCTTTGTGACCCAT               845   U   1832_845_U_F_1833_845_U_R   ACTGTCCCCTGCTGAACATC   AAATACAGCATGGCCCTGAG               845   V   1834_845_V_F_1835_845_V_R   CCCTTTGGGCTCTGGTTTAT   GGACGACTCCGTCCTCTCTA               845   V   1836_845_V_F_1837_845_V_R   GATTATCTGCGTGGTGGGTC   AGTTTCACCTTCCCCACCTT               845   W   1838_845_W_F_1839_845_W_R   TCTTTCAAACAGGCCTCTGG   ACCAGCTTTCACCTTGAGGG               845   X   1840_845_X_F_1841_845_X_R   TGATCCCATTGATCAGCATC   TTTGGAGATGTGGAGGTTCC               847   A   1925_847_A_F_1926_847_A_R   CTGTTTCCGGTTTTCCAGC   GACGAGAGATGCTGCTGTTG               847   A   2009_847_A_F_2010_847_A_R   CAGGAGCAGCAGCAACAA   TGGTCCTGCACTGACTTGAG               847   A   1929_847_A_F_1930_847_A_R   GGCTTCTCCATGCTGCTCT   CCACGCTGATCACCTGCT               847   A   1931_847_A_F_1932_847_A_R   TAAAGGTGCTGGACAAGTGG   CCTTTCTCCAGCAAAGGGA               847   B   1903_847_B_F_1904_847_B_R   ACCACCGTGCTCACCTACCT   AGCTGCTTGGATGGAGGAC               847   C   1905_847_C_F_1906_847_C_R   CTCTGTGGAGAGAGGCMCC   CAACCCCTCTAGGACCCTT               847   D   1907_847_D_F_1908_847_O_R   GGGGCCTAGGGATAGTCTCA   CTACCCTGTTCTTGCTCCCA               847   E   1909_847_E_F_1910_847_E_R   CCAAGTGCCTGACTTGGTTT   GGAGCAGGGACTTGTGTTTG               847   F   1911_847_F_F_1912_847_F_R   TCCTGGCTCTCTCUTCTGG   CTCTAAGGAGCGCAGGACAC               847   G   1913_847_G_F_1914_847_G_R   CTAACCTGCTTTCACCTCGC   CATTCAGCACACATGGCATC               847   H   1915_847_H_F_1916_847_H_R   AAGGGGTCTCTGCACCACTA   ACATTCTTGGAGGCCCATC               847   I   1917_847_I_F_1918_847_I_R   TAGGGAAGTTCATCGTTGGC   AGAAGGCTGGCTGTCCACT               847   J   1919_847_J_F_1920_847_J_R   CCTGTCCCCAACAAGAAAGA   TTTGCGCCAGATGAAGTATG               847   K   1921_847_K_F_1922_847_K_R   GAGCTCGAGGTGGAAGAAGA   CTCCTCCAGGTTGTAGGCTG               847   K   1923_847_K_F_1924_847_K_R   TCATCAGTGGGTACCAGCPA   TTTGGAGTGTTTCTGAGGGG               847   L   2030_847_L_F_2031_847_L_R   CCACCCTATCACGATTCCGT   GCAGTAACGGCTGCTGCTC               847   L   1933_847_L_F_1934_847_L_R   GTACGTGTCGGCCCTGA   ATAGCTGCGCTGCATGTCT               847   L   1935_847_L_F_1936_847_L_R   CCCATCAGTTACCGCCTG   CTCCTGCGTGGTCTCGTACT               847   L   1937_847_L_F_1938_847_L_R   GTACGAGACCACGCAGGAGT   TCAGCGACAGCGAGTCC               847   L   1939_847_L_F_1940_847_L_R   GTAGACCACGCAGGAGT   CCCAGGAAAGGTGTGCTCT               847   L   1941_847_L_F_1942_847_L_R   GGACTCGCTGTCGCTGAG   GCTGTGGCTGTCCAGTGAGTA               847   L   1943_847_L_F_1944_847_L_R   AGAGCACACCTTTCCTGGG   CTCCTTAAAGATAGTGGGGCG               803   B   2052_803_B_F_2053_803_B_R   GTGGCGGGGCTGAAGAAG   CCCTTGGTCTTCCCACCTG               803   C   2054_803_C_F_2055_803_C_R   GTGTCCTGATCACTTGGCCT   AGTGCCACCACCACACAGA               803   D   2056_803_D_F_2057_803_D_R   CCTGGTATGGGCTCTTAGGG   GTTCTGTCATCCCCTGCCT               803   E   2058_803_E_F_2059_803_E_R   AAGGGTGGGGAGGAGATGT   CAGAGAGCACCACTCACCAA               803   E   2060_803_E_F_2061_803_E_R   TCTGGGCGAGTGCATGAT   TTGGTCTGTGCAGTCTCCTG               803   F   2062_803_F_F_2063_803_F_R   AGGCCCGGTATGATGGCTT   GAGGTGAGGGTGGCAGGAAT               803   G   2064_803_G_F_2065_803_G_R   CGCTACTGGTGTGACCCAT   CCCAAGGGCATAGGTCTTCT               803   H   2066_803_H_F_2067_803_H_R   AGGGAAGGCACAGGACAGT   CATGTGCTCACCCCACAG               803   I   2068_803_I_F_2069_803_I_R   AAATACAAGAGTGGGGCTGC   CATTTGCCTCCGCAAGAG               803   J   2070_803_J_F_2071_803_J_R   ACCGTTTTGAGCCCACAG   GCTTGAGATGGGCAGAGAAC               803   K   2072_803_K_F_2073_803_K_R   CAGGTCACAGCAGGTCTGAG   GGACACGGGTGAGTCACTG               803   K   2074_803_K_F_2075_803_K_R   AGCTACGTGGAGGTGCTTGT   TGGGAGTCAGCGCTAGTGTA                  
 
     [0333] Comparative DNA sequencing was used to determine the sequence changes in Gene 803, Gene 845, Gene 847, Gene 874 and Gene 962. Variants detected by SSCP analysis in the initial set of asthmatic and normal individuals were analyzed by fluorescent sequencing on an ABI 377 automated sequencer (Perkin-Elmer Applied Biosystems Division). Sequencing was performed using Amersham Energy Transfer Dye Primer chemistry (Amersham-Pharmacia Biotech) following the standard protocol described by the manufacturer. Primers used for dye primer sequencing are shown in Table 4. The first column lists the genes targeted for sequencing. The second column list the specific exons sequenced. The third and fourth list the forward primer names and the forward primer sequences, respectively. The fifth and sixth columns list the reverse primer names and reverse primer sequences, respectively.  
               TABLE 4                          SEQUENCING PRIMERS                                     Gene   Exon   Forward Primer   Forward Sequence   Reverse Primer   Reverse Sequence               803   B   MDSeq_523_803_B_F   TCCCGCGGTAGACAATG   MDSeq_523_803_B_R   GAGAAGGAGGGGAGAGGTC               803   B   MDSeq_540_803_B_B_F   AGGGTCACCTCCACGACTC   MDSeq_540_803_B_R   CCCTTGGTCTTCCCACCT               803   B   MDSeq_575_803_B_F   AACTCACTGACAGAGGCGG   MDSeq_575_803_B_R   GTCCCTTGGTCTTCGCACC               803   B   MDSeq_659_803_B_F   TGTGCACGTGCGCTCTTC   MDSeq_659_803_B_R   GTCCCFrGGTCTTCCCACCT               803   B   MDSeq_660_803_B_F   GCTGAACACTTAGACGAAOTGGATT   MDSeq_660_803_B_R   GGCACACACGTATCTTAGGAAAG               803   E   MDSeq_510_803_E_F   CTGAGGAGCTTGGTCACCTC   MDSeq_510_803_E_R   GTTTGCCCTTAACAGGTGGA               803   F   MDSeq_511_803_F_F   GGAAAGGATCCAGGTGTG   MDSeq_511_803_F_R   CTCCAGTTTCTTCAGGTGG               803   G   MDSeq_512_803_G_F   CTGAAGGAGATCCAGGTGCT   MDSeq_512_803_G_R   CTGTCCTGTGCCTTCCCT               803   H   MDSeq_513_803_H_F   ATGCACAACCTCCTGGAGAC   MDSeq_513_803_H_R   GGCTGGGTGTTGACTGAGA               803   I   MDSeq_514_803_I_F   CCCAGTCTAGCTGTGTCCC   MDSeq_514_803_I_R   TGTCGGAAGATCGGAAGAC               803   K   MDSeq_515_803_K_F   CCAAGCTTCTCCCATCCT   MDSeq_515_803_K_R   CTCAGGGAGTACCTGAAGGG               845   D   MDSeq_426_845_D_F   CCAGTGTTTCCCTTCACC   MDSeq_426_845_D_R   CCAGCAATCTCACATCGAG               845   E   MDSeq_433_845_E_F   GGAGTGATGTTCCCATAGTG   MDSeq_433_845_E_R   ATGTGGGTAATTACATAAAGCAA               845   F   MDSeq_442_845_F_F   AATGACATCTTCCCTGCCC   MDSeq_442_845_F_R   ATGGCAGTCATCTCCTGA               845   H   MDSeq_427_845_H_F   CTCCAGCAATAACCAAATG   MDSeq_427_845_H_R   TGCTACTGCCACAGCCT               845   H   MDSeq_504845_H_F   TAGCATGGGTAAGGCGTG   MDSeq_504_845_H_R   GCCTTCTCTGCTCACTCCAC               845   I   MDSeq_428_845_I_F   CAAGGGTTAGAGGAAGGCA   MDSeq_428_845_I_R   CGTAGTTCAGGGCTCTGTCA               845   J   MDSeq_436_845_J_F   GTTGCCTCCTTCTGTTGGA   MDSeq_436_845_J_R   TGGGTACAGAGCGCATGTT               845   K   MDSeq_429_845_K_F   CCAAGGAATCAGCTATGGG   MDSeq_429_845_K_R   CTTCAGGGTTCCTGAGCTTG               845   O   MDSeq_443_845_O_F   TGAGAAGGCTGAAGGTG   MDSeq_443_845_O_R   CTTAGGGCCATTTGCATT               845   P   MDSeq_430_845_P_F   GTTGAGAATATGGGGATGGA   MDSeq_430_845_P_R   GAAATGACCCAAAAGGGCT               845   R   MDSeq_432_845_R_F   ACAGACACAGGCCACCAG   MDSeq_432_845_R_R   TGTGGATGCTCTGCAACA               845   U   MDSeq_444_845_U_F   GGCCAACTCTGTTTCCTTGA   MDSeq_444_845_U_R   ATGGTGGTGGGCACCTG               845   V   MDSeq_437_845_V_F   CTAAGAGCCTCTGTGGGC   MDSeq_437_845_V_R   GTTGCTCTAACCTGCTGTG               845   W   MDSeq_445_845_W_F   CAGCTTGCTCTCCTGACTT   MDSeq_445_845_W_R   GGGCACCPAGAAACATGAAT               845   X   MDSeq_446_845_X_F   GGCTGACCATGCTGTATTC   MDSeq_446_845_X_R   GAGGAGAAGCTGCCAGTCAC               847   A   MDSeq_438_847_A_F   GCATCCTCCTCCAGGTCC   MDSeq_438_847_A_R   GTACCTTGCCCTCCACCAC               847   A   MDSeq_457_847_A_F   AACAGCAGCATCTCTCGTC   MDSeq_457_847_A_R   CCATTCTCCACCACCTCG               847   A   MDSeq_475_847_A_F   GCATCCTCCTCCAGGTCC   MDSeq_475_847_A_R   GTACCTTGCCCTCCACCAC               847   B   MDSeq_439_847_B_F   GGCATGAAGGAAACTCTCCA   MDSeq_439_847_B_R   GGGTCTTCCACTGATCAAGC               847   C   MDSeq_465_847_C_F   GGACATGTGAGCAGCCACTA   MDSeq_465_847_C_R   TTCCAGGCCCAGATAACAA               847   D   MDSeq_466_847_D_F   GGTTGCACTGGGTAAACG   MDSeq_466_847_D_R   CCTAAAGGGTGTTGGTGAA               847   E   MDSeq_447_847_E_F   TTTCCCATCTTCCCTCACC   MDSeq_447_847_E_R   ACCTGCAGCCCTGAACTTT               847   F   MDSeq_467_847_F_F   GTTCAGGGCTGCAGGTAA   MDSeq_467_847_F_R   AGACCCTTTGGTACCCTCA               847   G   MDSeq_478_847_G_F   TCTCTAAAGAGCCTGCCCTG   MDSeq_478_847_G_R   GCCCTTCTGTTCATGAGCTT               847   H   MDSeq_468_847_H_F   CCACTCATGTGCTCTGG   MDSeq_468_847_H_R   CCATTCTTCGTCAGTGCC               847   I   MDSeq_479_847_I_F   GCTTGAGTACAGGGACGAGC   MDSeq_479_847_I_R   CATGGAAGTGAGCAAACCA               847   J   MDSeq_454_847_J_F   GGTTTGCTCACTTCCATGA   MDSeq_454_847_J_R   GTCTGAGCCTTTGTGCTG               847   K   MDSeq_448_847_K_F   CAGCCCTCCTTCTTCCAATA   MDSeq_448_847_K_R   ACTGGCCCAACTCTAGTCC               847   L   MDSeq_450_847_L_F   TCGAAGATCCTGAGCGAGT   MDSeq_450_847_L_R   GGTCACTCCTCCCTCTGC               847   L   MDSeq_451_847_L_F   CCCATTTATCAGTGGTTGC   MDSeq_451_847_L_R   CTACCCCTTCCCGGCTC               847   L   MDSeq_461_847_L_F   GACTTCCACTACTCGOTGGC   MDSeq_461_847_L_R   CCAGGAAAGGTGTGCTCT               847   L   MDSeq_469_847_L_F   GACAGCTACTATTACCCCGC   MDSeq_469_847_L_R   CGCCTTTGCCGTTAG               847   L   MDSeq_501_847_L_F   GCCTGACTTCTGACTCCCA   MDSeq_501_847_L_R   TCCTGCGTGGTCTCGTACT               847   L   MDSeq_502_847_L_F   GCGCAGCTATGACAGCTACTA   MDSeq_502_847_L_R   GGTCTCCTTAAAGATAGTGGG               847   L   MDSeq_503_847_L_F   GGACTCGCTGTCGCTGAG   MDSeq_503_847_L_R   CCGAAGGTGTAAATCAGGA               847   L   MDSeq_516_847_L_F   CCACAGACCATGTCATCAGG   MDSeq_516_847_L_R   CCGAAGCTGTAAATCAGGA               874   R   MDSeq_592_874_R_F   GGCCCGCTGACTAGGGAT   MDSeq_592_874_R_R   GCGCTACCAGGCAGGAC               874   S   MDSeq_615_874_S_F   CAGACCCTCAGAGCCACA   MDSeq_615_874_S_R   CATCGTGACCTTTCACCTTCA               874   T   MDSeq_616_874_T_F   GGATAAACGGGCTTTCCACA   MDSeq_616_874_T_R   TGTGTCACCTGAACTGTTTGC               874   T   MDSeq_681_874_T_F   GGATAAACGGGCTTTCCACA   MDSeq_681_874_T_R   TGTGTCACCTGAACTGTTTGC               874   T   MDSeq_701_874_T_F   CCTCACCTACTGCGGGACTT   MDSeq_701_874_T_R   GTGGACCGAGGAAGCAA               874   U   MDSeq_617_874_U_F   ACAGTGAAGGGAGGATGGG   MDSeq_617_874_U_R   GGCCCATGTGTGTAGGA               874   V   MDSeq_618_874_V_F   ACAAGAGAGGGCAGGGAGC   MDSeq_618_874_V_R   AACGTGCCCAGAGCTGAC               874   W   MDSeq_619_874_W_F   AGCCTTTGMAGCACTGGC   MDSeq_619_874_W_R   CCCATCATAAGTTAAGGAGCATCTG               874   X   MDSeq_620_874_X_F   CACAGTCATCAGCACCACCA   MDSeq_620_874_X_R   CGCCTCTGTAGGATMGCGG               874   Y   MDSeq_621_874_Y_F   GATTTCCCACACTTCATCATGG   MDSeq_621_874_Y_R   GCAGACCAAACTGACAAGG               874   Z   MDSeq_622_874_Z_F   GCAAGTCACGGTCAGACTGG   MDSeq_622_874_Z_R   GCCCACCAGGCTAAGAGGAT               874   Z   MDSeq_682_874_Z_F   AACAGGAAGAGGPATGAGGG   MDSeq_682_874_Z_R   CCATGACTCCTGTGGGAGC               962   D   MDSeq_858_962_D_F   TCGCTCCTTCCCTCTCCC   MDSeq_858_962_D_R   GACTCAGGAGCCGCCAGT               962   E   MDSeq_859_962_E_F   GAGGTGCAGGCTGGCTTCT   MDSeq_859_962_E_R   CGACGTAGAGACAGCTCCC               962   E   MDSeq_860_962_E_F   CGTGGTGTCGGCAGCTA   MDSeq_860_962_E_R   GGAGCACGAGGCTCACTAA               962   F   MDSeq_861_962_F_F   CTCTGGGACCACATGTTCA   MDSeq_861_962_F_R   CTGAGCCACTGAGACCG               962   G   MDSeq_862_962_G_F   TTCCTCTGCACCTCGCTTT   MDSeq_862_962_G_R   CACTCACOTCCGGCTAACA               962   H   MDSeq_863_962_H_F   AGTTGATGGTGACGCCTGG   MDSeq_863_962_H_R   CCGTGGCCTGGTATGTCTCT               962   I   MDSeq_864_962_I_F   CCTGTCAAAGACTGGAGCCC   MDSeq_864_962_I_R   CCACACCCTCACCCAGCTA               962   J   MDSeq_865_962_J_F   CTGCTGTCAGCCAGATGTC   MDSeq_865_962_J_R   GGGAAGACAGGAGACCACA               962   K   MDSeq_866_962_K_F   AGCAGGTAGATGGTCGGTG   MDSeq_866_962_K_R   CAGGTGTGCCCTOTCTCCTC               962   L   MDSeq_867_962_L_F   TGCAGCAGGGAAACTGAGG   MDSeq_867_962_L_R   CCTGCCTAGGACCACGTCT               962   M   MDSeq_868_962_M_F   CACCGTATGGGCMGGTCT   MDSeq_868_962_M_R   GGTGTGCTCCAGCATCAGA               962   N   MDSeq_869_962_N_F   GGCGGAGCTTCTGAAAGAAA   MDSeq_869_962_N_R   CCGAATGGTGCAC1TCACTT               962   O   MDSeq_870_962_O_F   GCCAATGAGGCCTGTCTTCT   MDSeq_870_962_O_R   CCTGCACCTCTCCAGAACT               962   O   MDSeq_907_962_O_F   GCATCTAGGGGCGAGGAG   MDSeq_907_962_O_R   TCCCAGGTAGGGTGAGGC               962   P   MDSeq_871_962_P_F   GCTCAGCAGAGCTGCCC   MDSec_871_962_P_R   GCCCTGCTAGGAACTTTAATGC               962   Q   MDSeq_872_962_Q_F   TTTCCCTCTCTGTCTGCCC   MDSeq_872_962_O_R   GTCTCAGGCTCCCAGCAC               962   R   MDSeq_873_962_R_F   GATGAGGCCAGGCAAGGT   MDSeq_873_962_R_R   CCGACTTAGGATTCTCCCTCC               962   S   MDSeq_874_962_S_F   GTGGGTCCTCAAAGCCAGAG   MDSeq_874_962_S_R   GCTGAGCAGAGGGACAGGTT               962   T   MDSeq_875_962_T_F   GTCGTGGCACAGAGGAAAC   MDSeq_875_962_T_R   TGTCCCTTCCTGGCTGTGA               962   U   MDSeq_876_962_U_F   GCTCACAGGAACCTCACCCT   MDSeq_876_962_U_R   GGTCCCTGCTGTGGCT               962   V   MDSeq_877_962_V_F   CCTGCCACCCTTATTGT   MDSeq_877_962_V_R   CTGCCCTGCAGCATCTTA               962   W   MDSeq_878_962_W_F   TAAGAGAAGGTGCACCGGG   MDSeq_878_962_W_R   GTCATTGCAGTGCTTGGCAT               962   W   MDSeq_908_962_W_F   GGTTCTCCAGGTGCTGCG   MDSeq_908_962_W_R   GCCAATGATCAGGGCAGAG               962   X   MDSeq_879_962_X_F   AGAGAGACAGGCATGTGGG   MDSeq_879_962_X_R   CGCTTCTCCATGCTCACAGA               962   Z   MDSeq_880_962_Y_F   CAGCGGAGGACCCTTTGTC   MDSeq_880_962_Y_R   CCACGACAGATCTTTGCCC               962   Z   MDSeq_881_962_Z_F   CTTTCTGCCTGGGCTCACTT   MDSeq_881_962_Z_R   GATTAGGTTGGGTGGCTGGA               962   Z   MDSeq_882_962_Z_F   GCTGTGCTGCAAGTCCTG   MDSeq_882_962_Z_R   GTATTTGGTCGCTCCTGGG                  
 
     [0334] Single nucleotide polymorphisms (SNPs) that were identified in Gene 803, Gene 845, Gene 847, Gene 874 and Gene 962 are shown in Table 5. The first and second columns list SNP identifier and gene names, respectively. The third column lists the exons that either contain the SNPs or are flanked by intronic sequences that contain the SNPs. The fourth column lists the PMP sites for the SNPs. The “−” symbols denote polymorphisms which are 5′ of the exon and are within the intronic region. The “−” polymorphisms are numbered going from the 3′ to 5′ direction. The “+” symbols denote polymorphisms which are 3′ of the exon and are within the intronic region. The “+” polymorphisms are numbered going from the 5′ to 3′ direction. The second, third, and fourth columns, combined, correspond to the SNP names as described herein, e.g., 845_D — +1, 845_D — −1 etc. It should be noted that the disclosed SNPs are referred to herein using both short (e.g., SNP D+1 of Gene 845 or 845_D+1) and long (e.g., Gene 845 D+1) nomenclature. The fifth column lists the localization of the SNPs to exon, intron, or UTR sequences. The sixth column lists the SNP reference sequences and illustrates the SNP nucleotide changes in boldface. The seventh column lists the base changes of the SNP sequences. If applicable, the eighth column lists the amino acid changes resulting from the SNP sequences. The coordinates of the SNP as it corresponds to the genomic sequence are contained in the ninth and ten columns. More particularly, the ninth lists the coordinate of the particular SNP in relation to the single genomic contig reference sequence. The genomic contigs used to create the reference sequence are listed in the tenth column of Tables 5. The genomic sequences and contig sequences with their respective accession numbers are listed in Table 2 and provided in SEQ ID. NOs. 1-9. Column eleven lists the coordinates of the SNP as it corresponds to the genomic contig and sequence listed in column 10. The SNPs identified in the cDNA contain a coordinate listed in the twelfth column. In some instances, alternate splice variants for Gene 803, Gene 847 and Gene 962 contain different coordinates for each. Thus, the respective SNP and coordinate for each splice variant is noted in Table 5. In addition, FIGS.  1 - 12  show the respective cDNA sequence and SNP location relating to Table 5. One skilled in the art could also take the reference sequence listed in column 6 in Table 5 and compare to the related sequence described in Table 2 using the appropriate Accession number. For example, one could use the program BLAST or ClustalW to perform an alignment and comparison to identify the specific location. One could identify the location of exonic SNPs using FIGS.  1 - 12  to locate the particular SNP location in the genes and proteins provided herein. One could identify the location of intronic SNPs using the relevant SEQ ID NO: 1-9 and the appropriate coordinates from column 9 of Table 5. For example, to find the location of SNP 803 E+1, one could look at SEQ ID NO:1 at the position indicated by Table 5, in this case coordinate 276365. Alternatively, one could use the coordinate given in column 11 of Table 5 and the appropriate sequence from Table 2 to find the location of a particular SNP.  
     [0335] SEQ ID NOs: 1-9 contain the genomic sequence of Gene 803, Gene 845, Gene 847, Gene 874 and Gene 962. The corresponding accession numbers for these sequences are located within Table 2. SEQ ID NO: 1 contains the genomic sequence of Gene 803. SEQ ID NOs: 2-5 taken together contain the genomic sequence of Gene 845. SEQ ID NOs: 6 and 7 taken together contain the genomic sequence of Gene 847. SEQ ID NO: 8 contains the genomic sequence of Gene 874. SEQ ID NO: 9 contains the genomic sequence of Gene 962.  
     [0336] FIGS.  1 - 12  contain the cDNA and protein sequences with the corresponding SNP locations boldfaced and underlined for Gene 803, Gene 845, Gene 847, Gene 874 and Gene 962. FIGS. 1 and 2 contain the cDNA sequence and protein for two alternate splice variants of Gene 803. FIG. 3 contains the cDNA sequence and protein of Gene 845. FIGS.  4 - 9  contain the six alternate splice variants of Gene 847. FIG. 10 contains the cDNA and protein sequence of Gene 874. FIGS. 11 and 12 contain the cDNA and protein sequence of two alternate splice variants of Gene 962. Table 2 also contains the corresponding accession numbers to the cDNA and protein sequences relating to FIGS.  1 - 12 .  
               TABLE 5                          Gene SNPs                                                                                                 Single                                                       contig                               PMP               AA   Genomic       Genomic           SNP   Gene   Exon   Site   Location   Sequence   PMP   change   coord   Contig used for coords   Coord   cDNA coord                                                                         1   803   E   +1   intron   CAGGGCAGGTCCAGGCCCTGCATGTGCTGAGTGCCGGGGAC   C&gt;T   N/A   276365   R31167 AC007292 R/C   11130                       2   803   E   +2   intron   AGGGCAGGTCCAGGCCCTGCATGTGCTGAGTGCCGGGGACG   M&gt;G   N/A   276366   R31167   11131               3   803   H   −1   intron   GGCCCCAGTCCCCTGTCCCCTCTCAGCCCCCTTGCCTCCTG   TC   N/A   278195   R31167   12960-12961                               del               4   803   H   +1   intron   GCAAGTGGGCAGCACACCTCGCTGTGGGGTGAGCACATGGC   G&gt;A   N/A   278474   R31167   13239               5   803   I   −1   intron   AGAGTGGGGCTGCCTCGGCCGTGACACGGGCTCGGTCCACT   G&gt;C   N/A   278990   R31167   13755               6   803   I   1   Exon   CCTAAGCGGGAGTATAAGCCCAAGCCCCGGGAGCCCTTTGA   C&gt;G   None   279072   R31167   13837   965(v1):629(v2)               7   803   K   1   Exon   GAGCTGGGCTTCCATGAGGGCGAOGTCATCACGCTGACCAA   C&gt;T   None   280049   R31167   14814   1184(v1),848(v2)               8   803   K   2   Exon   GGTACGAGGGCATGCTGGACGGCCAGTCGGGCTTCTTCCCG   G&gt;A   Gly&gt;Ser   280107   R31167   14872   1242(v1),906(v2)               9   803   K   3   Exon   GACGGCCAGTCGGGCTTCTTCCCGCTCAGCTACGTGGAGGT   C&gt;T   None   280124   R31167   14889   1259(v1),923(v2)               10   845   D   +1   intron   ATAACTTCTGTGTCAACGCCAGACGCAGGTGTCGCTGTTCT   A&gt;G       N/A   6E24AC008694   11667               11   845   D   −1   intron   GTGCTAGATCCTGTGCCCGACCCAGGGAGCCTGGTGCCGGC   C&gt;T       N/A   6E24AC008694 R/C   11484               12   845   D   1   Exon   GTTGTTGCTTTGAGCATCCACTCAAAGCTGAGCTCAGGGTA   C&gt;T   Leu&gt;Phe   N/A   6E24AC008694 R/C   11547    264               13   845   F   +1   intron   CTGAGGCTGCAGGTGGCACCGGGCACTCTCCCCAGGAATGG   G&gt;T       N/A   47B1136AC008676   5389               14   845   F   +2   intron   GTTTCAAGATAGACAAGGCTGAGGCAAGGACCTTGGGAAGG   G&gt;A       N/A   47B1136AC008676   5432               15   845   G   +1   intron   AGAAATCAACCTGGGGACAGGCGGTCCCCTCTGAGGTTGC   G&gt;T       N/A   47B1136AC008676   16370               16   845   H   +1   intron   GCTCACGCCTGTAATCCCAGCAC1TTGGGTGGGCAAGGCGG   C&gt;G       N/A   47B1136AC008676   17516               17   845   H   +2   intron   TTTGGGTGGGCPAGGCGGGTGGATCACCTGAGGTCAGGAGT   G&gt;A       N/A   4761136AC008676   17539               18   845   H   −1   intron   GGAAGGTGTTATATGAGTGATGGCCACCACAGCCAAGAACA   T&gt;C       N/A   47811.36 AC008676   17124               19   845   H   1   exon   AAGTATGTGGAGCTTTACCTCGTGGCTGATTATTTAGAGGT   C&gt;T       N/A   47811.36 AC008676   17324    725               20   845   I   −1   intron   TTAGAGGMGGCAATTCTACTCCGTGCATMTTAUGCATG   T&gt;C       N/A   4781129 AC008676   2204               21   845   J   −1   intron   CTTTTTAATCTCAAGCTCCACCAGAATGAAAGGGGGGGCT   C&gt;A       N/A   47811.29 AC008676   6416               22   845   J   1   exon   CTACCCTCTGGTCCTTTCTCAGTTGGAGGCGCAAGCTGCTT   A&gt;G   Ser&gt;Gly   N/A   4781129 AC008676   6601    927               23   845   K   −1   intron   AGAGGTGTGGTGAGCTGGAAGTTGTCCAGTTGGCCTGGTTA   G&gt;T       N/A   47811.29 AC008676   8658               24   845   K   −2   intron   GTATATTGTGGGAGATAAACGACCTTTCTCTCTCTCTTTGT   G&gt;A       N/A   47811.29 AC008676   8578               25   845   K   1   exon   GCACCACCATCGGCCTGGCCCCCCTCATGGCCATGTGCTCTCT   C&gt;T   Pro&gt;Ser   N/A   47811.29 AC008676   8855   1020               26   845   P   +1   intron   ATGAAATGAGGATGAACAAGCAGTTTCTGCTCTGTCCTCAC   C&gt;T       N/A   47811.40 AC008676   9688               27   845   R   −1   intron   ATATGTTCCAAGTGCAAAATCTTGCCTCCTACTCCCAACC   C&gt;T       N/A   47811.40 AC008676   12353               28   845   R   1   exon   CTGTGGGAAGAAGTGCAATGGCCATGGGGTGCGTGCTGGGT   G&gt;A   Gly&gt;Asp   N/A   47811.40 AC008676   12490   2056               29   847   A   −1   intron   GGCTGAGCGGCGGAGCCCCCCAAATGGCCTGGCCAGATGCG   C&gt;T       N/A   13185AC011379   20517               30   847   A   1   exon   GCCGCCACTGGAGAAGGGTCGGTGCAGCAGCTACAGCGACA   G&gt;A   Arg&gt;Gln   N/A   13185 A0011379   20585   278(v1-v6)               31   847   A   2   exon   GTACAGGGGCTGGTCCCAGCCGGCGGCTCCAGCTCCMCAG   C&gt;T       N/A   13185 AC011379   20955   648(v1-v6)               32   847   C   +1   intron   CAACAGCGGTAGGTGGGCCCAGACAGAGGGAAGGGTCCTAG   A&gt;G       N/A   35F21 AC008667   13697               33   847   O   −1   intron   ATGATTCCTGGGGCCTAGGGATAGTCTCAGTGCGTCACTGG   A&gt;C       N/A   35F21 AC008667   22708               34   847   E   +1   intron   CCTGCTCCT1AGAAAGCTTCTGGGTGCAGTCCCCCCAATGT   T&gt;C       N/A   35F21 AC008667   29093               35   847   J   +1   intron   CAGCCACAGGTAGGCACCACCAAGGCCCATGGTAACTTGTA   C&gt;T       N/A   35F21 AC008667   42223               36   847   J   −1   intron   GAAGGGGTGGGGGTTGATTTGCTGGAGCCATCGCTGCCCCA   G&gt;T       N/A   35F21 AC008667   41929               37   847   K   −1   intron   CGAGGTGGAAGAAAGAGCCAGGGAGGTCCATGGGACCACACC   G&gt;A       N/A   35F21 AC008667   42735               38   847   K   1   exon   CTACAACCTGGAGGAGCGGCGCAGGGCCACCGCGCCACCCT   G&gt;A   Arg&gt;His   N/A   35F21 AC008667   42974   1931(v1), 1913(v2),                                                   1955(v3),1937(v4),                                                   N/A(v5),N/A(v6)               39   874   R   +1   intron   GCTGGCCGTCCGGCGGCAGCTTGGGGAGTTCGGCACCGAGC   T&gt;C   N/A   82285   RP11-163F8   82285   N/A               40   874   R   1   exon   GCCCTTGACGTCAGAGTGTTTCTCCGCAGAGCCCGTGTCCTG   T&gt;G   Phe&gt;Leu   81990   RP11-163F8   81990      7               41   874   R   2   exon   CAGAGGCGGCCAGGGGAGCGCGCCGCCCCGCTCGGCCOTCC   C&gt;T   Arg&gt;Cys   82078   RP11-163F8   82078     95               42   874   S   +5   intron   TTTTCATGTATGTTTTAAAACATAAAATGTAAAATATTCTG   C&gt;G   N/A   250203   RP11-335L15   95682   N/A               43   874   S   +4   intron   TACTTTTCATGTATGTTTTAAAACATAAAATGTAAATATTA   A&gt;G   N/A   250200   RP11-335L15   95679   N/A               44   874   S   +3   intron   TAAAACTACTTTTCATGTATGTTTTAAAACATAAATGTA   G&gt;A   N/A   250194   RP11-335L15   95673   N/A               45   874   S   2   intron   GGAGAGGGCAACTGTTTTCCACTGGTCTCTGAGAATACTAC   A&gt;G   N/A   250142   RP11-335L15   95621   N/A               46   874   S   1   intron   AGTGTTCCCTTGGACATAAACATGTCTACCATATTAGAGG   C&gt;A   N/A   250088   RP11-335L15   95567   N/A               47   874   S   −1   intron   GCTGCTATAAAAATGAGACTCTCCACCTAAGTCAGGGAATG   C&gt;G   N/A   249852   RP11-335L15   95331   N/A               48   874   T   1   intron   TACTTTTAGTTTCTCTTTGATAGACATTTTAAGTTGGGTG   A&gt;G   N/A   264482   RP11-335L15   109961   N/A               49   874   T   −1   intron   ATACAGACTCAACCAAAAACCGGTATTCTAAAGCTCATCAT   C&gt;T   N/A   264294   RP11-335L15   109773   N/A               50   874   U   −2   intron   TCCTGCTTCATCCAGAACAGAATTGCTGTAATTCATTTTAA   A&gt;T   N/A   289067   RP11-335L15   134546   N/A               51   874   U   −1   intron   CCTGCTTCATCCAGAACAGAATTGCTGTAATTCA1TFrAAG   A&gt;G   N/A   289068   RP11-335L15   134547   N/A               52   874   U   1   exon   ACCATGTCAAAAATCCGTGGCCAGGAGAAGGGGCCAGGCTA   C&gt;T   None   289343   RP11-335L15   134822    409               53   874   V   −3   intron   TAAAGGAAAAAGTAACTGTTCCATTCTTGATGAGAGGTATT   C&gt;G   N/A   290091   RP11-335L15   135570   N/A               54   874   V   −2   intron   GGTATTTACCCTCTTAGGGGGCATTGAGTCTGTTGCCTGGA   G&gt;A   N/A   290126   RP11-335L15   135605   N/A               55   874   V   −1   intron   CCTCTTAGGGGGCATTGAGTCTGTTGCCTGGAGTGAACTGA   C&gt;G   N/A   290135   RP11-335L15   135614   N/A               56   874   X   −1   intron   TATGTATGAAACAGTAGTGGCTGTTTAGGGATGGTAACGTG   C&gt;A   N/A   294088   RP11-335L15   139567   N/A               57   874   X   1   exon   TACCACAAGCAGGCAGTCCAGATCCTGCAGCAAGTCACGGT   G&gt;A   None   294212   RP11-335L15   139691    865               58   874   Y   1   intron   TGTCAATCATCAGCACACACGAACACATTTTGTTTTGACCC   G&gt;A   N/A   296674   RP11-335L15   142153   N/A               59   874   Y   2   intron   TTTTGACCCTCCTTTGTGGTCGTAAATCGCCTTTCCTTGTC   C&gt;T   N/A   296706   RP11-335L15   142185   N/A               60   874   Z   1   exon   ATCCTCTTAGCCTGGTGGGCGTGGCATGTGCTTTTTAAAAC   G&gt;A   None   298855   RP11-335L15   144334   1430               61   962   E   +2   intron   CTCCGCTGCTCTCGCCTGGGTTFTGGAAAAGGGTTACCTGG   T&gt;C   N/A   7805   CTC-500G13   7805   N/A                                           AC008544               62   962   E   +1   intron   TGCGATGGGCTGGTGAGTACGCACTTCTCTAGCTCCTTCT   G&gt;C   N/A   7764   CTC-500G13   7764   N/A               63   962   E   2   Exon   ACGAGCCCGCAGGGCCGCCCCGGTCCGGACCCCGAGCTTCC   C&gt;T   Pro&gt;Leu   7493   CTC-500G13   7493   272(v1-v2)               64   962   E   3   Exon   AACGAGGAGGAGCCTGGCAGTCACCTCTTCTACAATGTCAC   T&gt;C   None   7542   CTC-500G13   7542   321(v1-v2)               65   962   G   +1   Intron   CTGAGGGGGCAGGGTGGGGCGGGGAGGGTCAACCAGGGGCT   G&gt;A   N/A   143815   CTC-500G13   143815   N/A               66   962   G   −1   Intron   TTTGCCCTGCCGCTGAAGACGGTGTCCTCTCCTGGCAGGGG   G&gt;A   N/A   143561   CTC-500G13   143561   N/A               67   962   G   1   Exon   GCCTCAGCCGCGCCCTGGGCGTCCTAGAGGAGCACGCCAAC   G&gt;A   Val&gt;Ile   143623   CTC-500G13   143623   733(v1-v2)               68   962   G   2   Exon   AGGGCACGCAGGCATGCTGCGGACGATGACTACAACATCGA   G&gt;A   None   143676   CTC-500G13   143676   786(v1-v2)               69   962   G   3   Exon   CCTTGCAGGGGCCTCCCTGGACAGCCTGGACAGCCTCAGCC   A&gt;G   Asp&gt;Gly   143591   CTC-500G13   143591   701(v1-v2)               70   962   G   4   Exon   CAGCCTGGACAGCCTCAGCCGCGCCCTGGGCGTCCTAGAGG   G&gt;A   Arg&gt;His   143612   CTC-500G13   143612   722(v1-v2)               71   962   G   5   Exon   TGGGCGTCCTAGAGGAGCACGCCAACAGCTCGAGGCGGAGG   G&gt;A   Ala&gt;Thr   143638   CTC-500G13   143638   748(v1-v2)               72   962   G   6   Exon   CAGTTCCACGGGAAGGAGCACGTACAGAAGTACCTGCTGAC   C&gt;T   None   143748   CTC-500G13   143748   858(v1-v2)               73   962   H   −1   Intron   CCCATTGGCAGAGCCAGAGCCAGTCCTAGGGCCTGTGGTTC   C&gt;T   N/A   170091   CTC-202F10   4024   N/A               74   962   H   1   Exon   TCCTTGGGTGCCCACATCAACGTGGTCCTGGTGCGGATCAT   C&gt;T   None   170183   CTC-202F10   4116   936(v1-v2)               75   962   H   +1   Intron   AGGTTCCTATAAGAAACAAGATCCCTGCTCCCTTTCACCCC   A&gt;G   N/A   170372   CTC-202F10   4305   N/A               76   962   H   2   Intron   GGTTCCTATAAGAAACAAGATCCCTGCTCCCTTTCACCCCT   T&gt;A   N/A   170373   CTC-202F10   4306   N/A               77   962   I   −1   Intron   CACTACAGCCTGCTCGGCCCCCCACTGGGCCACCAGGCGCC   C&gt;T   N/A   192358   CTC-202F10   26291   N/A               78   962   J   +1   Intron   CGTGTAAGTGGCCTGGGGAAGGGTGGGGCACAGAGGGGCCA   G&gt;A   N/A   196498   CTC-202F10   30431   N/A               79   962   J   1   Intron   GCCTGGGAGTTAGGCCAGGCCTCACCTTCCCGGCCAGGCTA   C&gt;T   N/A   196318   CTC-202F10   30251   N/A               80   962   J   1   Exon   TGCACCCTGAACCATGAGGACGGCTGCTCCTCAGCGTTTGT   C&gt;T   None   196436   CTC-202F10   30369   1194(v1-v2)               81   962   L   −2   Intron   GCCGCGCTGAAGGCTGCTCGCGGCACCGTGTGTCCCCCACA   C&gt;T   N/A   197649   CTC-202F10   31582   N/A               82   962   L   −1   Intron   CTGAAGGCTGCTCGCGGCACCGTGTGTCCCCCACAGCTCCT   C&gt;T   N/A   197655   CTC-202F10   31588   N/A               83   962   L   1   exon   TTCGCCCACGACTGGCCGGCGOTGCCCCAGCTCCCGGGACT   G&gt;A   None   197719   CTC-202F10   31652   1431(v1-v2)               84   962   L   2   Exon   CAGCTCCCGGGACTGCACTACTCCATGAACGAGCAATGCCG   C&gt;T   None   197746   CTC-202F10   31679   1458(v1-v2)               85   962   L   3   exon   GAGCAATGCCGCTTTGACTTCGGCCTGGGCTACATGATGTG   C&gt;T   None   197776   CTC-202F10 A0010216   31709   1488(v1-v2)               86   962   M   −1   Intron   CTTCACCACCCCAGAATCACAACACCCACCAGCCTCACGGG   A&gt;G   N/A   198901   CTC-202F10   32834   N/A               87   962   M   +1   Intron   GCACCTGGCAAGGTGAGGCAGCATCAAGGGCTCTTGGAGGG   G&gt;A   N/A   199161   CTC-202F10   33094   N/A               88   962   M   +2   Intron   AGGCAGCATCAAGGGCTCTTGGAGGGCAGCAGGGCAGAGGA   G&gt;C   N/A   199176   CTC-202F10   33109   N/A               89   962   M   +3   Intron   TAATTACCOCTCACACGCTGTACGCCGGAGCTGCCTCCACC   T&gt;C   N/A   199313   CTC-202F10   33246   N/A               90   962   O   −2   Intron   GAGCGCAGGACTGTCCCCACGGCCCGGTGTGAGGGTGAGTG   G&gt;A   N/A   211213   CTC-202F10   45146   N/A               91   962   O   −1   Intron   GTGAGGGTGAGTGGAGGGACTGGCTTCCTGTCTTTCAGCAT   T&gt;C   N/A   211241   CTC-202F10   45174   N/A               92   962   O   +1   Intron   GCAGCTGAGGGTCCAGGAGACCCTCTCCAGCCAGCCCTGTC   C&gt;T   N/A   211462   CTC-202F10   45395   N/A               93   962   P   −3   Intron   GCTCAGCAGAGCTGCCCCCCGGACACCTGAGACTTAGGGAT   G&gt;A   N/A   213243   CTC-202F10   47176   N/A               94   962   P   −2   Intron   AAGATCTCACAGGGCACCCGGGTGCTGCCTCTTTCCATG   G&gt;A   N/A   213294   CTC-202F10   47227   N/A               95   962   P   −1   Intron   TCTTTCCAATGGCACGGAGCGGCAAGGCCTTTGCTTTCTCC   G&gt;A   N/A   213324   CTC-202F10   47257   N/A               96   962   P   +1   Intron   TTCTGGGAGGCATCAGTGGGGGCTCAGCAGGCAGGCCCTAG   G&gt;A   N/A   213555   CTC-202F10   47488   N/A               97   962   Q   +1   Intron   ATGAAGCGCATGGTGCATGACGGGACGCGCTGCTCCTACAA   C&gt;T   N/A   215329   CTC-202F10   49262   N/A               98   962   Q   +2   Intron   GTACTGACCTCCCCCTTTTCGGGGTATTGGCAAGATGCATG   G&gt;A   N/A   215462   CTC-202P10   49395   N/A               99   962   Q   −1   Intron   GTGGGGACCCTTGTGGAAATTTCTCCTGCTTGGTGCCTCCT   T&gt;A   N/A   215171   CTC-202F10   49104   N/A               100   962   Q   1   Exon   TACTGCGAGTCCAGGGAGACCGGGGAGGTGGTGTCCATGAA   C&gt;T   None   215293   CTC-202F10   49226   1992(v1), N/A(v2)               101   962   Q   2   Exon   ACTGCGAGTCCAGGGAGACCGGGGAGGTGGTGTCCATGAAG   G&gt;A   Gly&gt;Arg   215294   CTC-202F10   49227   1993(v1), N/A(v2)               102   962   S   −1   Intron   AGGGTCCTGGGAGAGCCTCCGGAGGAGCTGCCTTCAAGAGC   G&gt;C   N/A   218885   CTC-202F10   52818   N/A               103   962   T   −2   Intron   CCAGTGGGCCTGGGTCCTGCTCTTGGGTGACCACAACGGGG   T&gt;C   N/A   221154   CTC-202F10   55087   N/A               104   962   T   −1   Intron   ACGGGGGACTTGGTCGGCCATTCTCAGCCGTCAAGAACCT   A&gt;G   N/A   221189   CTC-202F10   55122   N/A               105   962   U   1   Exon   CATCCCGGTGGGAGACACCCGGGTCTCACTGACGTACAAAT   G&gt;A   Arg&gt;Gln   223199   CTC-202F10   57132   2480(v1), N/A(v2)               106   962   U   2   Exon   GAGGACTCACTGAATGTCGACGACACAACGTCCTGGAAGA   C&gt;T   None   223251   CTC-202F10   57184   2532(v1), N/A(v2)               107   962   V   +1   Intron   GCAGCCCACCCCTCCTTGCACCCTCGGGCAGGGCATGCTGC   C&gt;T   N/A   225111   CTC-202F10   59044   N/A               108   962   V   +1   Intron   CCCACTAGAGGAGACAGGCCAGGGGCCACCAGGGGCTCCCG   A&gt;G   N/A   225340   CTC-202F10   59273   N/A               109   962   V   +2   Intron   GCCTGGGCCTGGCATCATCCGAGGCATTTGACCAAGTCTCT   G&gt;A   N/A   225397   CTC-202F10   59330   N/A               110   962   Y   +1   Intron   GATCTCGTCAAGTAACCGACCCGTTTATAACTCTGCCTCTG   C&gt;T   N/A   229644   CTC-202F10   63577   N/A               111   962   Y   +2   intron   GTGACCGTTTTCTCCCGGGCCTCTGAGCTCGGCGTCCGCTC   C&gt;G   N/A   229782   CTC-202F10   63715   N/A               112   962   Z   1   Exon   TGGAAGATGAAGTCCAGCCACCCAACCTATCCCTCGACGA   C&gt;T   Pro&gt;Ser   237321   CTC-202F10   71254   3529(v1), N/A(v2)               113   962   Z   2   exon   CCACCGCCTGGGAAGCACAACGACAGGACGTGTTCATGCC   C&gt;T   None   237134   CTC-202F10   71067   3342(v1), N/A(v2)                  
 
     Example 6  
     [0337] Allele Specific Assay  
     [0338] Once variants were confirmed by sequencing, rapid allele specific assays were designed to type and diagnose more than 400 individuals (&gt;200 cases and &gt;200 controls) for use in the association studies. All coding SNPs (cSNPs) that resulted in an amino acid change were typed. Neutral polymorphisms were typed if: 1) the polymorphism was present in an exon lacking a cSNP; 2) the polymorphism was present in an exon containing a cSNP, but the two polymorphisms were observed to have different frequencies; or 3) the polymorphism was in an intronic region adjacent to an exon without a cSNP. If results from the association studies appeared positive, additional neutral polymorphisms were typed.  
     [0339] Three types of allele specific assays (ASAs) were used. If the SNP resulted in a mutation that created or abolished a restriction site, RFLPs were obtained from PCR products that spanned the variants, and were subsequently analyzed. If the polymorphism did not result in an RFLP, allele-specific oligonucleotide or exonuclease proofreading assays were used. For the allele-specific oligonucleotide assays, PCR products that spanned the polymorphism were electrophoresed on agarose gels and transferred to nylon membranes by Southern blotting. Oligomers 16-20 bp in length were designed such that the middle base was specific for each variant. The oligomers were labeled and successively hybridized to the membrane in order to determine genotypes.  
     [0340] Table 7, below, shows the information for the ASAs. The first column lists the SNP names. The second column lists the specific assays used (RFLP, ASO, an alternate method). The third column lists the enzymes used in the RFLP assay (described below). The fourth and fifth columns list the sequences of the oligos used in the ASO assay (described below). In addition, Table 7 contains the nucleic acid base change at the SNP location and if applicable, the corresponding amino acid change of the resulting protein.  
               TABLE 7                          Allele Specific Assays                                         SNP   ASA Type   RFLP Enzyme   ASO Oligo1   ASO Oligo2   Base change   A.A. change               845_D_+1   RFLP   Mspl           A&gt;G                   845_D_−1   ASO       GTGCCCGACCCAGGGA   GTGCCCGATCCAGGGAGC   C&gt;T               845_D_1   ASO       AGCATCCACTCAAAGCTG   AGCATCCATTCAAAGCTGA   C&gt;T   Leu&gt;Phe               845_F_+1   RFLP   Bsp12861           G&gt;T               845_G_+1   ASO       GGGGACAGGCTTGTCC   CCTGGGGACAGTCTTGTCCCCT   G&gt;T               845_H_+1   RFLP   BsaJL           C&gt;G               845_H_+2   RFLP   Alwl           G&gt;A               845_H_−1   RFLP   Mscl           T&gt;C               845_I_−1   ASO       GCAATTCTACTCCGTGCATAAT   CAATTCTACCCCGTGCATA   T&gt;C               845_J_−1   RFLP   Msll           C&gt;A               845_J_1   RFLP   Odel           A&gt;G   Ser&gt;Gly               845_K_−1   RFLP   Tsp5091           G&gt;T               845_K_−2   ASO       GAGATAAACAACCTTTCTCT   GAGATAAACGACCTTTCTCT   G&gt;A               845_K_1   RFLP   Sau961           C&gt;T   Pro&gt;Ser               845_P_+1   RFLP   AlwNl           C&gt;T               845_R_−1   RFLP   Tsp5091           C&gt;T               845_R_1   RFLP   Mscl           G&gt;A   Gly&gt;Asp               847_A_1   ASO       GAAGGGTCGGTGCAGCA   GAAGGGTCAGTGCAGCAGC   G&gt;A   Arg&gt;Gln               847_A_2   RFLP   Pvull           C&gt;T               847_C_+1   RFLP   Ncil           A&gt;G               847_D_−1   ASO       GGGCCTAGGGATAGTCTCAG   CCTAGGGCTAGTCTCAGT   A&gt;C               847_E_+1   RFLP   Ncil           T&gt;C               847_J_+1   ASO       GCACCACCAAGGCCCAT   AGGCACCACTAAGGCCCAT   C&gt;T               847_K_1   ASO       GAGCGGCGCAGGGCC   GGAGCGGCACAGGGCCA   G&gt;A   Arg&gt;His               803_E_+2   RFLP   Nlalll           A&gt;G               803_H_+1   ASO       ACACCTCGCTGTGGGGT   GCACACCTCACTGTGGGG   G&gt;A               803_H_−1   ASO       GTCCCCTCTCAGCCCCC   GTCCCCTCAGCCCCC   TC del               803_I_−1   RFLP BslEl           G&gt;C               803_I_1   ASO       GTATAAGCCCAAGCCCC   GTATAAGCCGAAGCCCC   C&gt;G               803_K_3   RFLP   Hboll           G&gt;A   Gly&gt;Ser               803_K_3   Mboll               C&gt;T               962_E_+2   ASO       CGCCTGGGTTTTGGAAAAG   CGCCTGGGCTTTGGAAAA   T&gt;C               962_E_2   At Meth           C&gt;T Pro&gt;Leu               962_E_3   RFLP   Hphl           T&gt;C               962_G_1   RFLP   BsaHl           G&gt;A   Val&gt;Ile               962_G_2   RFLP   Pstl           G&gt;A               962_G_4   RFLP   BstUl           G&gt;A   Arg&gt;His               962_G_5   RFLP   Cac8l           G&gt;A   Ala&gt;Thr               962_G_6   RFLP   HpyCH4lV           C&gt;T               962_H_+2   RFLP   Dpnll           T&gt;A               962_J_1   Alt Meth           C&gt;T               962_L_2   Alt Meth           C&gt;T               962_M_+2   RFLP   Taq           G&gt;C               962_P_−2   RFLP   AlwNl           G&gt;A               962_Q_−1   RFLP   Asp5091           T&gt;A   G&gt;C               962_S_−2   RFLP   Slyl           T&gt;C               962_U_1   RFLP   Aval           G&gt;A   Arg&gt;Gln               962_U_2   RFLP   Hincll           C&gt;T               962_V_+2   RFLP   Styl           G&gt;A               962_V_−1   ASO       CCCGAGGGTGCAAGGA   GCCCGAGGATGCAAGGAG   C&gt;T               962_Z_1   Alt Meth           C&gt;T   Pro&gt;Ser               874_R_+1   RFLP   BstNl           T&gt;C               874_R_1   Alt Meth           T&gt;G   Phe&gt;Leu               874_R_2   ASO       GGGAGCGCGCC   GCCGGGGAGCGTGCCGCCC   C&gt;T   Arg&gt;Cys               874_S_+1   RFLP   Nlalll           C&gt;A               874_S_+3   Alt Meth           G&gt;A               874_T_−1   RFLP   Hpall           C&gt;T               874_U_−2   Alt Meth           A&gt;T               874_V_−1   RFLP   Hinfl           C&gt;G               874_X_1   RFLP   Dpnll           G&gt;A               874_Y_+2   It Meth           C&gt;T               874_Z_1   It Meth           G&gt;A                  
 
     [0341] 1. RFLP Assay: The amplicon containing the polymorphism was PCR amplified using primers that generated fragments for sequencing (sequencing primers) or SSCP (SSCP primers). The appropriate population of individuals was PCR amplified in 96-well microtiter plates. Enzymes were purchased from NEB. The restriction cocktail containing the appropriate enzyme for the particular polymorphism was added to the PCR product. The reaction was incubated at the appropriate temperature according to the manufacturer&#39;s recommendations for 2-3 hr, followed by a 4° C. incubation. After digestion, the reactions were size fractionated using the appropriate agarose gel depending on the assay specifications (2.5%, 3%, or Metaphor, FMC Bioproducts). Gels were electrophoresed in 1× TBE buffer at 170 V for approximately 2 hr. The gel was illuminated using UV, and the image was saved as a Kodak 1D file. Using the Kodak 1D image analysis software, the images were scored and the data was exported to Microsoft® Excel (http://www.microsoft.com).  
     [0342] 2. ASO assay: The amplicon containing the polymorphism was PCR amplified using primers that generated fragments for sequencing (sequencing primers) or SSCP (SSCP primers). The appropriate population of individuals was PCR amplified in 96-well microtiter plates and re-arrayed into 384-well microtiter plates using a Tecan Genesis RSP200. The amplified products were loaded onto 2% agarose gels and size fractionated at 150V for 5 min. The DNA was transferred from the gel to Hybond N+ nylon membrane (Amersham-Pharmacia) using a Vacuum blotter (Bio-Rad). The filter containing the blotted PCR products was transferred to a dish containing 300 ml pre-hybridization solution (5×SSPE (pH 7.4), 2% SDS, 5× Denhardt&#39;s). The filter was incubated in pre-hybridization solution at 40° C. for over 1 hr. After pre-hybridization, 10 ml of the pre-hybridization solution and the filter were transferred to a washed glass bottle. The allele-specific oligonucleotides (ASO) were designed to contain the polymorphism in the middle of the nucleotide sequence. The size of the oligonucleotide was dependent upon the GC content of the sequence around the polymorphism. Those ASOs that had a G or C polymorphism were designed so that the T m  was between 54-56° C. Those ASOs that had an A or T polymorphism were designed so that the T m  was between 60-64° C. All oligonucleotides were phosphate-free at the 5′ ends and purchased from GibcoBRL. For each polymorphism, 2 ASOs were designed to yield one ASO for each strand.  
     [0343] The ASOs that represented each polymorphism were resuspended at a concentration of 1 μg/μl. Each ASO was end-labeled with γ-ATP 32  (6000 Ci/mmol) (NEN) using T4 polynucleotide kinase according to manufacturer recommendations (NEB). The end-labeled products were removed from the unincorporated γ-ATP 32  using a Sephadex G-25 column according to the manufacturer&#39;s instructions (Amersham-Pharmacia). The entire end-labeled product of one ASO was added to the bottle containing the appropriate filter and 10 ml hybridization solution. The hybridization reaction was placed in a rotisserie oven (Hybaid) and left at 40° C. for a minimum of 4 hr. The other ASO was stored at −20° C.  
     [0344] After the prerequisite hybridization time had elapsed, the filter was removed from the bottle and transferred to 1 L of wash solution (0.1×SSPE (pH 7.4) and 0.1% SDS) pre-warmed to 45° C. After 15 min, the filter was transferred to another liter of wash solution (0.1×SSPE (pH 7.4) and 0.1% SDS) pre-warmed to 50° C. After 15 min, the filter was wrapped in Saran Wrap®, placed in an autoradiograph cassette, and an X-ray film (Kodak) was placed on top of the filter. Typically, an image was visible within 1 hr. After an image was captured on film following the 50° C. wash, images were captured following wash steps at 55° C., 60° C. and 65° C. The best image was selected.  
     [0345] The ASO was removed from the filter by adding 1 L of boiling strip solution (0.1×SSPE (pH 7.4) and 0.1% SDS). This was repeated two more times. After removing the ASO, the filter was pre-hybridized in 300 ml pre-hybridization solution (5×SSPE (pH 7.4), 2% SDS, and 5× Denhardt&#39;s) at 40° C. for over 1 hr. The second end-labeled ASO corresponding to the other strand was removed from storage at −20° C. and thawed at RT. The filter was placed into a glass bottle along with 10 ml hybridization solution and the entire end-labeled product of the second ASO. The hybridization reaction was placed in a rotisserie oven (Hybaid, http://www.hybaid.co.uk) and left at 40° C. for a minimum of 4 hr. After the hybridization, the filter was washed at various temperatures and images captured on film as described above. The best image for each ASO was converted into a digital image by scanning the film into Adobe® Photoshop®. These images were overlaid using Graphic Converter, and the overlaid images were scored.  
     [0346] 3. Exonuclease Proofreading Assay: Exonuclease Proofreading Assays (EPAs) were also employed (see U.S. Pat. No. 5,391,480). Briefly, primers corresponding to the polymorphisms of interest were designed to contain fluorescent tags at the 3′ ends. The primers were designed such that the 3′ ends contained the variant or consensus nucleotides. Mismatched bases at the 3′ ends were removed by an exonuclease proof-reading enzyme (Pwo DNA polymerase; Roche, Germany; Cat. No. 1-644-855) in the PCR reaction. Where bases were matched, the resulting PCR products contained the tagged bases. The tagged bases were detected by gel electrophoresis or florescent polarization  
     Example 7  
     [0347] Association Study Analysis  
     [0348] 1. Case-Control Study All the genes listed in Tables 1 and 2 are involved in asthma and related disorders however, in order to determine which polymorphisms in candidate genes are strongly associated with the asthma phenotype, association studies were performed using a case-control design. In a well-matched design, the case-control approach is more powerful than the family based transmission disequilibrium test (TDT) (N. E. Morton and A. Collins, 1998,  Proc. Natl. Acad. Sci. USA  95:11389-93). Case-control studies are, however, sensitive to population admixture.  
     [0349] To avoid issues of population admixture, which can bias case-control studies, unaffected controls were collected in both the US and the UK. A total of three hundred controls were collected, 200 in the UK and 100 in the US. Inclusion into the study required that the control individual was 1) negative for asthma (as determined by self-report of never having asthma); 2) had no first-degree relatives with asthma; and 3) was negative for eczema and symptoms indicative of atopy for the past 12 months. Data from an abbreviated questionnaire similar to that administered to the affected sib pair families were collected. Results from skin prick tests to 4 common allergens were also collected. The results of the skin prick tests were used to select a subset of controls that were most likely to be asthma and atopy negative.  
     [0350] A subset of unrelated cases was selected from the affected sib pair families based on the evidence for linkage at the chromosomal location near a given gene. One affected sib demonstrating identity-by-descent (IBD) at the appropriate marker loci was selected from each family. As the appropriate cases may vary for each gene in the region, a larger collection of individuals who were IBD across a larger interval was genotyped. A subset of this collection was used in the analyses. Over 100 IBD affected individuals and 200 controls were compared for allele and genotype frequencies.  
     [0351] For each polymorphism, the frequency of the alleles in the control and case populations was compared using a Fisher&#39;s exact test. A mutation that increased susceptibility to the disease was expected to be more prevalent in the cases than in the controls, while a protective mutation was expected to be more prevalent in the control group. Similarly, the genotype frequencies of the SNPs were compared between cases and controls. P-values for the allele and genotype tests are tabulated. A small p-value was deemed indicative of an association between the SNPs and the disease phenotype. The analysis was repeated for the US and UK populations, separately, to correct for genetic heterogeneity. The association tables under this section show the least frequent base or allele in the control population. Table 5 above shows all base changes for the particular SNP location. Therefore, a particular allele or base may be discussed as significant in the text under this section but the particular base is not reported in the tables below. Thus, the base at the particular location can be identified using Table 5.  
     [0352] 2. Association test with individual SNPs: Fourteen SNPs in Gene 845, seven SNPs in Gene 847, four SNPs in Gene 874, six SNPs in Gene 803 and 16 SNPs in Gene 962 were typed. Four separate phenotypes were used in these analyses: asthma, bronchial hyper-responsiveness, total IgE, and specific IgE.  
     [0353] a. Asthma Phenotype: Frequencies and p-values for all typed SNPs are shown in Tables 9, 10, and 11 for the combined population and for the UK and US populations, separately. Column 1 lists the SNP names, which were derived from the gene numbers and closest exons. Column 2 lists the allele name. Columns 3 and 4 list the control (“CNTL”) allele frequencies and sample sizes (“N”), respectively. Columns 5 and 6 list the affected individuals (“CASE”) allele frequencies and sample sizes (“N”), respectively. Columns 7 and 8 list the p-values for the comparison between the case and control allele and genotype frequencies, respectively. A single SNP in Gene 845 reached statistical significance in the US population alone for the allele test: SNP P+1. For this SNP, 17.4% of the cases were carriers of the T allele, whereas the T allele was observed in only 6.5% of the controls (allele test p=0.0366). A single SNP in Gene 803 reached statistical significance in the combined and the US population alone for both the allele and the genotype tests: SNP K 2. For this SNP, 2.1% of the cases in the combined population were carriers of the A allele, whereas the A allele was observed in only 0.2% of the controls (combined: allele test p=0.0242, genotype test p=0.0237; US: allele test p=0.0475, genotype test p=0.0467). Five SNPs in Gene 962 reached statistical significance in the combined and the US population alone for both the allele and the genotype tests: 15.2% of the cases were carriers of the C allele in SNP M+2, whereas the C allele was observed in only 13.2% of the controls (US: genotype test p=0.0336), 40.5% of the cases were carriers of the A allele in SNP P−2, whereas the A allele was observed in only 22.4% of the controls (US: allele test p=0.0286, genotype test p=0.0227), 39.1% of the cases were carriers of the A allele in SNP Q−1, whereas the A allele was observed in only 21.7% of the controls (US: allele test p=0.0218, genotype test p=0.0375), 39.6% of the cases were carriers of the T allele in SNP U 2, whereas the T allele was observed in only 21.7% of the controls (US: allele test p=0.0225, genotype test p=0.0284) and 73.5% of the cases were carriers of the C allele in SNP V−1, whereas the C allele was observed in only 65.2% of the controls SNP V−1 (combined: allele test p=0.0383).  
               TABLE 9                          ASSOCIATION ANALYSIS OF ASTHMA PHENOTYPE       COMBINED US/UK POPULATION       Combined US &amp; UK                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   14.8%   216   12.5%   100   0.4634   0.7361       845_R_−1   T   28.7%   214   26.0%   102   0.5070   0.7697       845_P_+1   T   6.5%   217   9.5%   105   0.1998   0.3027       845_K_1   T   0.2%   210   0.0%   96   1.0000   1.0000       845_K_−2   A   28.9%   216   24.0%   98   0.2103   0.4160       845_J_1   G   34.5%   210   38.8%   103   0.3296   0.5664       845_J_−1   C   37.1%   217   38.5%   104   0.7940   0.4453       845_I_−1   C   12.8%   191   11.5%   104   0.6962   0.6932       845_H_+1   G   19.6%   217   14.9%   104   0.1559   0.3133       845_H_−1   T   45.2%   217   44.2%   103   0.8650   0.7396       845_G_+1   T   13.2%   216   13.9%   104   0.8053   0.5846       845_F_+1   T   18.4%   215   17.6%   105   0.9130   0.5565       845_D_1   T   0.2%   216   1.0%   99   0.2339   0.2335       845_D_−1   T   9.9%   217   11.1%   99   0.6727   0.4308       847_K_1   A   4.9%   214   5.7%   97   0.6976   0.6900       847_J_+1   T   4.9%   216   2.3%   109   0.1394   0.1312       847_E_+1   C   12.6%   210   13.1%   107   0.9001   0.4982       847_D_−1   C   16.9%   210   18.3%   93   0.7272   0.8153       847_C_+1   G   17.9%   209   20.8%   108   0.3932   0.1700       847_A_2   T   6.7%   217   7.3%   109   0.7457   0.7365       847_A_1   A   1.0%   192   0.5%   103   0.6625   0.6610       874_R_+1   T   39.9%   202   35.6%   94   0.3645   0.2706       874_S_+1   A   39.5%   214   41.9%   99   0.5993   0.8366       874_T_−1   T   48.6%   213   50.0%   100   0.7971   0.8135       874_V_−1   G   17.6%   216   19.5%   100   0.5803   0.3894       803_K_3   T   0.9%   218   1.2%   121   0.7046   0.7035       803_K_2   A   0.2%   217   2.1%   121   0.0242   0.0237       803_I_1   G   28.2%   195   26.9%   119   0.7829   0.4504       803_I_−1   C   0.2%   217   0.0%   118   1.0000   1.0000       803_H_+1   A   25.2%   218   24.4%   119   0.8524   0.9029       803_E_+2   A   44.2%   208   45.3%   118   0.8060   0.8313       962_E_3   C   35.6%   212   38.7%   115   0.4455   0.4859       962_E_+2   C   12.7%   217   10.4%   120   0.4558   0.3772       962_G_4   A   13.6%   202   9.6%   114   0.1641   0.2877       962_G_1   A   27.2%   217   34.3%   121   0.0541   0.0932       962_G_2   A   7.6%   217   7.6%   118   1.0000   0.4312       962_G_6   T   20.4%   194   17.8%   115   0.4632   0.7068       962_H_+2   A   41.5%   217   39.5%   119   0.6236   0.6019       962_M_+2   C   12.7%   213   9.3%   113   0.2455   0.1865       962_P_−2   A   23.8%   214   25.4%   114   0.7026   0.4231       962_Q_−1   A   23.7%   215   25.7%   115   0.6345   0.7013       962_S_−1   C   11.4%   215   7.6%   119   0.1388   0.3757       962_U_1   A   3.0%   214   3.5%   115   0.8173   0.8144       962_U_2   T   23.8%   212   25.0%   118   0.7763   0.8883       962_V_−1   T   34.8%   187   26.5%   115   0.0383   0.0954       962_V_+2   A   4.5%   209   2.5%   119   0.2117   0.5991       962_Z_1   T   31.9%   216   33.1%   121   0.7970   0.1515                  
 
     [0354]               TABLE 10                          ASSOCIATION ANALYSIS OF ASTHMA       PHENOTYPE UK POPULATION       UK population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   13.6%   140   13.9%   79   1.0000   0.9021       845_R_−1   T   26.6%   137   25.3%   79   0.8205   0.9047       845_P_+1   T   6.4%   140   7.3%   82   0.7005   0.6394       845_K_I   T   0.4%   135   0.0%   73   1.0000   1.0000       845_K_−2   A   27.0%   139   24.0%   77   0.5669   0.8306       845_J_1   G   36.6%   134   37.5%   80   0.9176   0.9804       845_J_−1   C   37.5%   140   40.1%   81   0.6126   0.5300       845_I_−1   C   12.6%   127   11.1%   81   0.7575   0.9186       845_H_+1   G   19.3%   140   16.0%   81   0.4428   0.5503       845_H_−1   T   43.6%   140   42.6%   81   0.9207   0.9647       845_G_+1   T   3.2%   140   14.8%   81   0.6688   0.6235       845_F_+1   T   8.8%   138   18.3%   82   1.0000   0.9315       845_D_1   T   0.0%   140   1.3%   78   0.1275   0.1270       845_D−—1   T   9.3%   140   10.3%   78   0.7377   0.7237       847_K_1   A   3.6%   139   4.8%   73   0.6053   0.5980       847_J_+1   T   2.9%   139   2.4%   85   1.0000   1.0000       847_E_+1   C   12.8%   133   14.1%   85   0.7727   0.2313       847_D_−1   C   16.5%   136   21.2%   73   0.2351   0.2901       847_C_+1   G   17.8%   132   22.9%   85   0.2175   0.0894       847_A_2   T   5.4%   140   7.1%   85   0.5400   0.5266       847_A_1   A   1.3%   120   0.6%   83   0.6479   0.6462       874_R_+1   T   41.5%   129   35.8%   74   0.2918   0.4463       874_S_+1   A   38.0%   137   42.3%   78   0.4122   0.5428       874_T_−1   T   48.9%   136   50.6%   79   0.7645   0.9496       874_V_−1   G   16.9%   139   19.6%   79   0.5164   0.5248       803_K_3   T   1.1%   140   1.5%   99   0.6955   0.6940       803_K_2   A   0.4%   139   1.5%   99   0.3124   0.3104       803_I_1   G   28.6%   117   24.7%   97   0.3827   0.2487       803_I_−1   C   0.4%   139   0.0%   96   1.0000   1.0000       803_H_+1   A   25.7%   140   25.3%   97   1.0000   0.8747       803_E_+2   A   42.4%   132   46.9%   96   0.3903   0.5906       962_E_3   C   36.8%   136   36.4%   92   1.0000   0.9824       962_E_+2   C   12.5%   140   9.9%   96   0.4621   0.7476       962_G_4   A   14.0%   132   10.6%   90   0.3105   0.4407       962_G_1   A   25.2%   139   33.5%   97   0.0502   0.1164       962_G_2   A   6.4%   140   7.4%   94   0.7106   0.5925       962_G_6   T   21.7%   129   16.8%   92   0.2261   0.3013       962_H_+2   A   43.6%   140   39.5%   95   0.3926   0.5214       962_M_+2   C   12.4%   137   7.8%   90   0.1221   0.3225       962_P_−2   A   24.6%   136   22.0%   93   0.5757   0.7940       962_Q_−1   A   24.8%   139   22.3%   92   0.5776   0.8022       962_S_−1   C   10.9%   137   6.3%   95   0.1006   0.2430       962_U_1   A   3.7%   136   3.7%   94   1.0000   1.0000       962_U_2   T   25.0%   136   21.3%   94   0.3727   0.7464       962_V_−1   T   34.4%   122   27.2%   92   0.1154   0.0909       962_V_+2   A   4.5%   134   2.6%   95   0.4526   0.7627       962_Z_1   T   30.0%   140   35.1%   97   0.2713   0.0735                    
     [0355]               TABLE 11                          ASSOCIATION ANALYSIS OF ASTHMA       PHENOTYPE US POPULATION       US population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   17.1%   76   7.1%   21   0.1433   0.3391       845_R_−1   T   32.5%   77   28.3%   23   0.7180   0.5080       845_P_+1   T   6.5%   77   17.4%   23   0.0366   0.1001       845_K_1   T   0.0%   75   0.0%   23   1.0000   1.0000       845_K_−2   A   32.5%   77   23.8%   21   0.3465   0.5335       845_J_1   G   30.9%   76   43.5%   23   0.1542   0.2183       845_J_−1   C   36.4%   77   32.6%   23   0.7267   0.8775       845_I_−1   C   13.3%   64   13.0%   23   1.0000   0.8761       845_H_+1   G   20.1%   77   10.9%   23   0.1915   0.3921       845_H_−1   T   48.1%   77   50.0%   22   0.8652   0.3922       845_G_+1   T   13.2%   76   10.9%   23   0.8037   1.0000       845_F_+1   T   17.5%   77   15.2%   23   0.8253   0.6755       845_D_1   T   0.7%   76   0.0%   21   1.0000   1.0000       845_D_−1   T   11.0%   77   14.3%   21   0.5906   0.2681       847_K_1   A   7.3%   75   8.3%   24   0.7617   0.7545       847_J_+1   T   8.4%   77   2.1%   24   0.1949   0.1777       847_E_+1   C   12.3%   77   9.1%   22   0.7899   0.7751       847_D_−1   C   17.6%   74   7.5%   20   0.1431   0.3321       847_C_+1   G   18.2%   77   13.0%   23   0.5067   0.9089       847_A_2   T   9.1%   77   8.3%   24   1.0000   1.0000       847_A_1   A   0.7%   72   0.0%   20   1.0000   1.0000       874_R_+1   T   37.0%   73   35.0%   20   0.8552   0.4180       874_S_+1   A   42.2%   77   40.5%   21   0.8620   0.7119       874_T_−1   T   48.1%   77   47.6%   21   1.0000   0.8466       874_V_−1   G   18.8%   77   19.1%   21   1.0000   0.7254       803_K_3   T   0.6%   78   0.0%   22   1.0000   1.0000       803_K_2   A   0.0%   78   4.6%   22   0.0475   0.0467       803_I_1   G   27.6%   78   36.4%   22   0.2666   0.4829       803_I_−1   C   0.0%   78   0.0%   22   1.0000   1.0000       803_H_+1   A   24.4%   78   20.5%   22   0.6895   0.9220       803_E_+2   A   47.4%   76   38.6%   22   0.3902   0.6005       962_E_3   C   33.6%   76   47.8%   23   0.0842   0.0784       962_E_+2   C   13.0%   77   12.5%   24   1.0000   0.2140       962_G_4   A   12.9%   70   6.3%   24   0.2910   0.5390       962_G_1   A   30.8%   78   37.5%   24   0.3839   0.5552       962_G_2   A   9.7%   77   8.3%   24   1.0000   1.0000       962_G_6   T   17.7%   65   21.7%   23   0.5195   0.7849       962_H_+2   A   37.7%   77   39.6%   24   0.8654   1.0000       962_M_+2   C   13.2%   76   15.2%   23   0.8065   0.0336       962_P_−2   A   22.4%   78   40.5%   21   0.0286   0.0227       962_Q_−1   A   21.7%   76   39.1%   23   0.0218   0.0375       962_S_−1   C   12.2%   78   12.5%   24   1.0000   0.8999       962_U_1   A   1.9%   78   2.4%   21   1.0000   1.0000       962_U_2   T   21.7%   76   39.6%   24   0.0225   0.0284       962_V_−1   T   35.4%   65   23.9%   23   0.1995   0.1120       962_V_+2   A   4.7%   75   2.1%   24   0.6823   0.6754       962_Z_1   T   35.5%   76   25.0%   24   0.2185   0.2520                    
     [0356] b. Bronchial Hyper-responsiveness: The analyses were repeated using asthmatic children with borderline to severe BHR (PC 20 ≦16 mg/ml) or PC 20 (16), as described in the Linkage Analysis section. (Example 3). First, sibling pairs were identified where both sibs were affected and satisfied this new criterion. Of these pairs, one sib was included in the case/control analyses if they showed evidence of linkage at the gene of interest. This phenotype was more restrictive than the Asthma yes/no criteria; hence the number of cases included in the analyses was reduced by approximately 57%. Where the PC 20 (16) subgroup represented a more genetically homogeneous sample, one could expect an increase in the effect size compared to the one observed in the original set of cases. However, the reduction in sample size could result in estimates that were less accurate. This, in turn, could obscure a trend in allele frequencies in the control group, the original set of cases, and the PC 20 (16) subgroup. In addition, the reduction in sample size could induce a reduction in power (and increase in p-values) in spite of the larger effect size.  
     [0357] The significance levels (p-values) for allele and genotype association of all typed SNPs to the BHR phenotype are shown in Tables 12, 13, and 14 for the combined population and for the UK and US populations separately. Allele frequencies are also included in the tables.  
               TABLE 12                          ASSOCIATION ANALYSIS OF BHR       PHENOTYPE COMBINED US/UK POPULATION       Combined US &amp; UK                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   14.8%   216   8.3%   42   0.1227   0.3809       845_R_−1   T   28.7%   214   23.8%   42   0.4252   0.5421       845_P_+1   T   6.5%   217   12.5%   44   0.0715   0.0821       845_K_1   T   0.2%   210   0.0%   42   1.0000   1.0000       845_K_−2   A   28.9%   216   20.9%   43   0.1469   0.3532       845_J_1   G   34.5%   210   50.0%   43   0.0098   0.0151       845_J_−1   C   37.1%   217   31.8%   44   0.3952   0.5677       845_I_−1   C   12.8%   191   12.5%   44   1.0000   0.9160       845_H_+1   G   19.6%   217   12.5%   44   0.1325   0.2182       845_H_−1   T   45.2%   217   37.5%   44   0.1969   0.1876       845_G_+1   T   13.2%   216   14.8%   44   0.7318   0.4613       845_F_+1   T   18.4%   215   18.2%   44   1.0000   0.3208       845_D_1   T   0.2%   216   1.2%   42   0.2993   0.2996       845_D_−1   T   9.9%   217   20.2%   42   0.0139   0.0083       847_K_1   A   4.9%   214   3.6%   42   0.7810   0.7754       847_J_+1   T   4.9%   216   1.1%   47   0.1502   0.1413       847_E_+1   C   12.6%   210   12.0%   46   1.0000   0.9162       847_D_−1   C   16.9%   210   15.1%   43   0.7526   0.7296       847_C_+1   G   17.9%   209   17.7%   48   1.0000   1.0000       847_A_2   T   6.7%   217   4.2%   48   0.4852   0.4699       847_A_1   A   1.0%   192   1.0%   48   1.0000   1.0000       874_R_+1   T   39.9%   202   29.3%   46   0.0738   0.1586       874_S_+1   A   39.5%   214   42.6%   47   0.6422   0.8454       874_T_−1   T   48.6%   213   46.9%   48   0.8214   0.4498       874_V_−1   G   17.6%   216   18.8%   48   0.7695   0.6737       803_K_3   T   0.9%   218   2.6%   58   0.1647   0.1635       803_K_2   A   0.2%   217   0.9%   58   0.3776   0.3779       803_I_1   G   28.2%   195   28.5%   58   1.0000   1.0000       803_I_−1   C   0.2%   217   0.0%   56   1.0000   1.0000       803_H_+1   A   25.2%   218   21.9%   57   0.5414   0.6420       803_E_+2   A   44.2%   208   46.5%   57   0.6722   0.8478       962_E_3   C   35.6%   212   34.7%   49   0.9071   0.9013       962_E_+2   C   12.7%   217   8.7%   52   0.3128   0.5841       962_G_4   A   13.6%   202   8.3%   48   0.1756   0.2010       962_G_1   A   27.2%   217   29.8%   52   0.6260   0.5278       962_G_2   A   7.6%   217   8.8%   51   0.6830   0.6707       962_G_6   T   20.4%   194   15.3%   49   0.3165   0.4404       962_H_+2   A   41.5%   217   35.3%   51   0.2641   0.2847       962_M_+2   C   12.7%   213   8.2%   49   0.2968   0.2530       962_P_−2   A   23.8%   214   21.4%   49   0.6921   0.4539       962_Q_−1   A   23.7%   215   21.9%   48   0.7901   0.6686       962_S_−1   C   11.4%   215   7.8%   51   0.3741   0.4768       962_U_1   A   3.0%   214   4.9%   51   0.3617   0.3548       962_U_2   T   23.8%   212   20.0%   50   0.5095   0.7424       962_V_−1   T   34.8%   187   26.5%   49   0.1476   0.2075       962_V_+2   A   4.5%   209   2.0%   51   0.3973   0.5039       962_Z_1   T   31.9%   216   37.5%   52   0.2968   0.2436                  
 
     [0358]               TABLE 13                          ASSOCIATION ANALYSIS OF BHR       PHENOTYPE UK POPULATION       UK population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   13.6%   140   9.7%   36   0.4358   0.9112       845_R_−1   T   26.6%   137   21.4%   35   0.4437   0.3471       845_P_+1   T   6.4%   140   10.8%   37   0.2120   0.2939       845_K_1   T   0.4%   135   0.0%   35   1.0000   1.0000       845_K_−2   A   27.0%   139   18.1%   36   0.1299   0.3673       845_J_1   G   36.6%   134   51.4%   36   0.0296   0.0475       845_J_−1   C   37.5%   140   33.8%   37   0.5899   0.8093       845_I_−1   C   12.6%   127   12.2%   37   1.0000   1.0000       845_H_+1   G   19.3%   140   14.9%   37   0.4994   0.7871       845_H_−1   T   43.6%   140   33.8%   37   0.1454   0.1454       845_G_+1   T   13.2%   140   14.9%   37   0.7047   0.5094       845_F_+1   T   18.8%   138   18.9%   37   1.0000   0.5839       845_D_1   T   0.0%   140   1.4%   36   0.2045   0.2045       845_D_−1   T   9.3%   140   20.8%   36   0.0120   0.0069       847_K_1   A   3.6%   139   4.4%   34   0.7250   0.7214       847_J_+1   T   2.9%   139   1.3%   39   0.6900   0.6859       847_E_+1   C   12.8%   133   14.1%   39   0.8486   0.4668       847_D_−1   C   16.5%   136   18.6%   35   0.7215   0.8339       847_C_+1   G   17.8%   132   21.3%   40   0.5130   0.6295       847_A_2   T   5.4%   140   5.0%   40   1.0000   1.0000       847_A_1   A   1.3%   120   1.3%   40   1.0000   1.0000       874_R_+1   T   41.5%   129   30.8%   39   0.1116   0.2579       874_S_+1   A   38.0%   137   44.9%   39   0.2947   0.4876       874_T_−1   T   48.9%   136   47.5%   40   0.8989   0.7399       874_V_−1   G   16.9%   139   18.8%   40   0.7379   0.8269       803_K_3   T   1.1%   140   3.1%   49   0.1828   0.1812       803_K_2   A   0.4%   139   0.0%   49   1.0000   1.0000       803_I_1   G   28.6%   117   25.5%   49   0.5933   0.8653       803_I_−1   C   0.4%   139   0.0%   47   1.0000   1.0000       803_H_+1   A   25.7%   140   21.9%   48   0.4953   0.7481       803_E_+2   A   42.4%   132   49.0%   48   0.2821   0.4597       962_E_3   C   36.8%   136   32.1%   42   0.5150   0.7793       962_E_+2   C   12.5%   140   10.0%   45   0.5802   0.9068       962_G_4   A   14.0%   132   8.5%   41   0.2549   0.2572       962_G_1   A   25.2%   139   28.9%   45   0.4922   0.3482       962_G_2   A   6.4%   140   10.2%   44   0.2444   0.2270       962_G_6   T   21.7%   129   16.7%   42   0.3540   0.2230       962_H_+2   A   43.6%   140   35.2%   44   0.1748   0.2934       962_M_+2   C   12.4%   137   7.1%   42   0.2352   0.5149       962_P_−2   A   24.6%   136   19.3%   44   0.3843   0.6062       962_Q_−1   A   24.8%   139   20.2%   42   0.4650   0.5108       962_S_−1   C   10.9%   137   6.8%   44   0.3107   0.7140       962_U_1   A   3.7%   136   4.5%   44   0.7524   0.7481       962_U_2   T   25.0%   136   17.4%   43   0.1868   0.3713       962_V_−1   T   34.4%   122   25.0%   42   0.1357   0.1353       962_V_+2   A   4.5%   134   2.3%   44   0.5311   0.7988       962_Z_1   T   30.0%   140   40.0%   45   0.0924   0.0467                    
     [0359]               TABLE 14                          ASSOCIATION ANALYSIS OF       BHR PHENOTYPE US POPULATION       US population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   17.1%   76   0.0%   6   0.2168   0.2965       845_R_−1   T   32.5%   77   35.7%   7   0.7742   0.6790       845_P_+1   T   6.5%   77   21.4%   7   0.0801   0.1254       845_K_1   T   0.0%   75   0.0%   7   1.0000   1.0000       845_K_−2   A   32.5%   77   35.7%   7   0.7742   0.6790       845_J_1   G   30.9%   76   42.9%   7   0.3787   0.5066       845_J_−1   C   36.4%   77   21.4%   7   0.3830   0.5888       845_I_−1   C   13.3%   64   14.3%   7   1.0000   0.7087       845_H_+1   G   20.1%   77   0.0%   7   0.0752   0.1660       845_H_−1   T   48.1%   77   57.1%   7   0.5841   0.7769       845_G_+1   T   13.2%   76   14.3%   7   1.0000   0.7054       845_F_+1   T   17.5%   77   14.3%   7   1.0000   1.0000       845_D_1   T   0.7%   76   0.0%   6   1.0000   1.0000       845_D_−1   T   11.0%   77   16.7%   6   0.6307   0.6162       847_K_1   A   7.3%   75   0.0%   8   0.6027   0.5892       847_J_+1   T   8.4%   77   0.0%   8   0.6146   0.3488       847_E_+1   C   12.3%   77   0.0%   7   0.3721   0.3417       847_D_−1   C   17.6%   74   0.0%   8   0.0779   0.2076       847_C_+1   G   18.2%   77   0.0%   8   0.0770   0.1869       847_A_2   T   9.1%   77   0.0%   8   0.3669   0.3423       847_A_1   A   0.7%   72   0.0%   8   1.0000   1.0000       874_R_+1   T   37.0%   73   21.4%   7   0.3818   0.6663       874_S_+1   A   42.2%   77   31.3%   8   0.4382   0.6119       874_T_−1   T   48.1%   77   43.8%   8   0.7977   0.6137       874_V_−1   G   18.8%   77   18.8%   8   1.0000   0.7807       803_K_3   T   0.6%   78   0.0%   9   1.0000   1.0000       803_K_2   A   0.0%   78   5.6%   9   0.1034   0.1034       803_I_1   G   27.6%   78   44.4%   9   0.1714   0.2111       803_I_−1   C   0.0%   78   0.0%   9   1.0000   1.0000       803_H_+1   A   24.4%   78   22.2%   9   1.0000   0.8463       803_E_+2   A   47.4%   76   33.3%   9   0.3214   0.6636       962_E_3   C   33.6%   76   50.0%   7   0.2478   0.1841       962_E_+2   C   13.0%   77   0.0%   7   0.3791   0.1892       962_G_4   A   12.9%   70   7.1%   7   1.0000   1.0000       962_G_1   A   30.8%   78   35.7%   7   0.7656   0.6406       962_G_2   A   9.7%   77   0.0%   7   0.6172   0.3425       962_G_6   T   17.7%   65   7.1%   7   0.4658   1.0000       962_H_+2   A   37.7%   77   35.7%   7   1.0000   0.2819       962_M_+2   C   13.2%   76   14.3%   7   1.0000   0.1122       962_P_−2   A   22.4%   78   40.0%   5   0.2469   0.2330       962_D_−1   A   21.7%   76   33.3%   6   0.4707   0.3338       962_S_−1   C   12.2%   78   14.3%   7   0.6849   0.1564       962_U_1   A   1.9%   78   7.1%   7   0.2932   0.2955       962_U_2   T   21.7%   76   35.7%   7   0.3150   0.2666       962_V_−1   T   35.4%   65   35.7%   7   1.0000   1.0000       962_V_+2   A   4.7%   75   0.0%   7   1.0000   1.0000       962_Z_1   T   35.5%   76   21.4%   7   0.3845   0.7311                    
     [0360] For the BHR phenotype, two SNPs in Gene 845 reached statistical significance in the combined and the UK population alone for both the allele and the genotype tests: 50.0% of the cases in the combined population were carriers of the G allele in SNP J 1, whereas the G allele was observed in only 34.5% of the controls (combined: allele test p=0.0098, genotype test p=0.0151; UK: allele test p=0.0296, genotype test p=0.0475) and 20.2% of the cases in the combined population were carriers of the T allele in SNP D−1, whereas the T allele was observed in only 9.9% of the controls (combined: allele test p=0.0139, genotype test p=0.0083; UK: allele test p=0.0120, genotype test p=0.0069).  
     [0361] c. Total IqE: The analyses were performed using asthmatic children with elevated total IgE levels, as described in the Linkage Analysis section (Example 3). First, sibling pairs were identified where both sibs were affected and satisfied this new criterion. Of these pairs, one sib was included in the case/control analyses if they showed evidence of linkage at the gene of interest. This phenotype was more restrictive than the Asthma yes/no criteria; hence the number of cases included in the analyses was reduced by approximately 42%.  
     [0362] The significance levels (p-values) for allele and genotype association of all typed SNPs to the IgE phenotype are shown in Tables 15, 16, and 17 for the combined population and for the UK and US populations, separately. Allele frequencies are also included in the tables.  
               TABLE 15                          ASSOCIATION ANALYSIS OF TOTAL IgE       PHENOTYPE COMBINED US/UK POPULATION       Combined US &amp; UK                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   14.8%   216   14.1%   64   0.8877   1.0000       845_R_−1   T   28.7%   214   21.1%   64   0.0901   0.2230       845_P_+1   T   6.5%   217   10.8%   65   0.1257   0.2366       845_K_1   T   0.2%   210   0.0%   59   1.0000   1.0000       845_K_−2   A   28.9%   216   22.1%   61   0.1677   0.3144       845_J_1   G   34.5%   210   40.0%   65   0.2952   0.4631       845_J_−1   C   37.1%   217   40.0%   65   0.6062   0.7606       845_I_−1   C   12.8%   191   11.5%   65   0.7609   0.8852       845_H_+1   G   19.6%   217   16.2%   65   0.4431   0.5034       845_H_−1   T   45.2%   217   41.4%   64   0.4795   0.7050       845_G_+1   T   13.2%   216   14.6%   65   0.6628   0.8129       845_F_+1   T   18.4%   215   18.5%   65   1.0000   0.5492       845_D_1   T   0.2%   216   0.8%   62   0.3966   0.3969       845_D_−1   T   9.9%   217   12.1%   62   0.5050   0.4794       847_K_1   A   4.9%   214   5.0%   60   1.0000   1.0000       847_J_+1   T   4.9%   216   3.0%   67   0.4732   0.4625       847_E_+1   C   12.6%   210   15.2%   66   0.4629   0.3564       847_D_−1   C   16.9%   210   17.9%   56   0.7795   0.6697       847_C_+1   G   17.9%   209   21.5%   65   0.3696   0.0887       847_A_2   T   6.7%   217   7.5%   67   0.7007   0.8391       847_A_1   A   1.0%   192   0.8%   62   1.0000   1.0000       874_R_+1   T   39.9%   202   32.0%   64   0.1181   0.3281       874_S_+1   A   39.5%   214   40.4%   68   0.8413   0.9644       874_T_−1   T   48.6%   213   50.0%   69   0.8447   0.9345       874_V_−1   G   17.6%   216   21.0%   69   0.3785   0.1676       803_K_3   T   0.9%   218   2.2%   67   0.3637   0.3609       803_K_2   A   0.2%   217   1.5%   67   0.1402   0.1397       803_I_1   G   28.2%   195   28.8%   66   0.9113   0.5678       803_I_−1   C   0.2%   217   0.0%   64   1.0000   1.0000       803_H_+1   A   25.2%   218   23.5%   66   0.7311   0.7690       803_E_+2   A   44.2%   208   45.4%   65   0.8402   0.9639       962_E_3   C   35.6%   212   32.1%   70   0.4753   0.4122       962_E_+2   C   12.7%   217   6.8%   73   0.0677   0.1672       962_G_4   A   13.6%   202   7.1%   70   0.0487   0.0749       962_G_1   A   27.2%   217   37.0%   73   0.0280   0.0472       962_G_2   A   7.6%   217   7.7%   71   1.0000   1.0000       962_G_6   T   20.4%   194   16.2%   71   0.3205   0.0794       962_H_+2   A   41.5%   217   34.0%   72   0.1170   0.2501       962_M_+2   C   12.7%   213   10.7%   70   0.6553   0.5397       962_P_−2   A   23.8%   214   25.4%   69   0.7323   0.4327       962_Q_−1   A   23.7%   215   24.6%   69   0.8195   0.8627       962_S_−1   C   11.4%   215   8.3%   72   0.3507   0.6768       962_U_1   A   3.0%   214   3.6%   70   0.7821   0.7789       962_U_2   T   23.8%   212   23.9%   71   1.0000   0.8648       962_V_−1   T   34.8%   187   30.4%   69   0.3994   0.2858       962_V_+2   A   4.5%   209   3.5%   72   0.8112   1.0000       962_Z_1   T   31.9%   216   31.5%   73   1.0000   0.5168                  
 
     [0363]               TABLE 16                          ASSOCIATION ANALYSIS OF TOTAL IgE       PHENOTYPE UK POPULATION       UK population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   13.6%   140   15.4%   52   0.6245   0.8181       845_R_−1   T   26.6%   137   20.2%   52   0.2308   0.3992       845_P_+1   T   6.4%   140   9.4%   53   0.3784   0.3276       845_K_1   T   0.4%   135   0.0%   47   1.0000   1.0000       845_K_−2   A   27.0%   139   21.0%   50   0.2842   0.4390       845_J_1   G   36.6%   134   40.6%   53   0.4798   0.7186       845_J_−1   C   37.5%   140   40.6%   53   0.6392   0.8105       845_I_−1   C   12.6%   127   11.3%   53   0.8603   1.0000       845_H_+1   G   19.3%   140   16.0%   53   0.5564   0.4068       845_H_−1   T   43.6%   140   39.6%   53   0.4918   0.8043       845_G_+1   T   13.2%   140   16.0%   53   0.5116   0.7663       845_F_+1   T   18.8%   138   18.9%   53   1.0000   0.8226       845_D_1   T   0.0%   140   1.0%   51   0.2670   0.2670       845_D_−1   T   9.3%   140   11.8%   51   0.4474   0.5389       847_K_1   A   3.6%   139   3.2%   47   1.0000   1.0000       847_J_+1   T   2.9%   139   2.8%   54   1.0000   1.0000       847_E_+1   C   12.8%   133   17.9%   53   0.2494   0.0776       847_D_−1   C   16.5%   136   21.6%   44   0.3355   0.1746       847_C_+1   G   17.8%   132   24.5%   53   0.1502   0.0228       847_A_2   T   5.4%   140   7.4%   54   0.4740   0.4606       847_A_1   A   1.3%   120   0.9%   53   1.0000   1.0000       874_R_+1   T   41.5%   129   33.3%   54   0.1597   0.3907       874_S_+1   A   38.0%   137   39.5%   57   0.8191   0.5707       874_T_−1   T   48.9%   136   52.6%   58   0.5794   0.7577       874_V_−1   G   16.9%   139   19.8%   58   0.4743   0.4157       803_K_3   T   1.1%   140   2.6%   58   0.3645   0.3612       803_K_2   A   0.4%   139   1.7%   58   0.2083   0.2077       803_I_1   G   28.6%   117   26.3%   57   0.7033   0.3961       803_I_−1   C   0.4%   139   0.0%   55   1.0000   1.0000       803_H_+1   A   25.7%   140   23.7%   57   0.7028   0.8814       803_E_+2   A   42.4%   132   48.2%   56   0.3091   0.5632       962_E_3   C   36.8%   136   31.0%   58   0.2974   0.5165       962_E_+2   C   12.5%   140   7.4%   61   0.1645   0.3555       962_G_4   A   14.0%   132   7.8%   58   0.0904   0.1867       962_G_1   A   25.2%   139   34.4%   61   0.0695   0.1331       962_G_2   A   6.4%   140   7.6%   59   0.6660   0.6550       962_G_6   T   21.7%   129   14.4%   59   0.1218   0.0239       962_H_+2   A   43.6%   140   35.8%   60   0.1834   0.2912       962_M_+2   C   12.4%   137   8.6%   58   0.3811   0.6573       962_P_−2   A   24.6%   136   21.2%   59   0.5173   0.8032       962_Q_−1   A   24.8%   139   20.7%   58   0.4355   0.7382       962_S_−1   C   10.9%   137   6.7%   60   0.2008   0.4682       962_U_1   A   3.7%   136   3.4%   59   1.0000   1.0000       962_U_2   T   25.0%   136   19.5%   59   0.2970   0.6158       962_V_−1   T   34.4%   122   31.0%   58   0.5516   0.2373       962_V_+2   A   4.5%   134   3.3%   60   0.7845   1.0000       962_Z_1   T   30.0%   140   33.6%   61   0.4837   0.2793                    
     [0364]               TABLE 17                          ASSOCIATION ANALYSIS OF TOTAL IgE       PHENOTYPE US POPULATION       US population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   17.1%   76   8.3%   12   0.3763   0.6251       845_R_−1   T   32.5%   77   25.0%   12   0.6371   0.8973       845_P_+1   T   6.5%   77   16.7%   12   0.1002   0.1818       845_K_1   T   0.0%   75   0.0%   12   1.0000   1.0000       845_K_−2   A   32.5%   77   27.3%   11   0.8075   1.0000       845_J_1   G   30.9%   76   37.5%   12   0.6376   0.7377       845_J_−1   C   36.4%   77   37.5%   12   1.0000   1.0000       845_I_−1   C   13.3%   64   12.5%   12   1.0000   0.7982       845_H_+1   G   20.1%   77   16.7%   12   1.0000   1.0000       845_H_−1   T   48.1%   77   50.0%   11   1.0000   0.7010       845_G_+1   T   13.2%   76   8.3%   12   0.7426   1.0000       845_F_+1   T   17.5%   77   16.7%   12   1.0000   0.8486       845_D_1   T   0.7%   76   0.0%   11   1.0000   1.0000       845_D_−1   T   11.0%   77   13.6%   11   0.7202   0.7075       847_K_1   A   7.3%   75   11.5%   13   0.4387   0.4273       847_J_+1   T   8.4%   77   3.8%   13   0.6961   0.6829       847_E_+1   C   12.3%   77   3.8%   13   0.3158   0.2829       847_D_−1   C   17.6%   74   4.2%   12   0.1308   0.3152       847_C_+1   G   18.2%   77   8.3%   12   0.3780   0.6757       847_A_2   T   9.1%   77   7.7%   13   1.0000   1.0000       847_A_1   A   0.7%   72   0.0%   9   1.0000   1.0000       874_R_+1   T   37.0%   73   25.0%   10   0.3317   0.7405       874_S_+1   A   42.2%   77   45.5%   11   0.8201   0.4213       874_T_−1   T   48.1%   77   36.4%   11   0.3647   0.3947       874_V_−1   G   18.8%   77   27.3%   11   0.3924   0.2974       803_K_3   T   0.6%   78   0.0%   9   1.0000   1.0000       803_K_2   A   0.0%   78   0.0%   9   1.0000   1.0000       803_I_1   G   27.6%   78   44.4%   9   0.1714   0.2111       803_I_−1   C   0.0%   78   0.0%   9   1.0000   1.0000       803_H_+1   A   24.4%   78   22.2%   9   1.0000   0.8463       803_E_+2   A   47.4%   76   27.8%   9   0.1375   0.3483       962_E_3   C   33.6%   76   37.5%   12   0.8172   0.5320       962_E_+2   C   13.0%   77   4.2%   12   0.3160   0.2803       962_G_4   A   12.9%   70   4.2%   12   0.3133   0.5253       962_G_1   A   30.8%   78   50.0%   12   0.1014   0.0734       962_G_2   A   9.7%   77   8.3%   12   1.0000   1.0000       962_G_6   T   17.7%   65   25.0%   12   0.4013   0.5214       962_H_+2   A   37.7%   77   25.0%   12   0.2614   0.6315       962_M_+2   C   13.2%   76   20.8%   12   0.3451   0.0838       962_P_−2   A   22.4%   78   50.0%   10   0.0130   0.0116       962_Q_−1   A   21.7%   76   45.5%   11   0.0309   0.0261       962_S_−1   C   12.2%   78   16.7%   12   0.5172   0.5073       962_U_1   A   1.9%   78   4.5%   11   0.4129   0.4158       962_U_2   T   21.7%   76   45.8%   12   0.0201   0.0233       962_V_−1   T   35.4%   65   27.3%   11   0.6278   0.8097       962_V_+2   A   4.7%   75   4.2%   12   1.0000   1.0000       962_Z_1   T   35.5%   76   20.8%   12   0.2438   0.4274                    
     [0365] For the total IgE phenotype, a single SNP in Gene 847 reached statistical significance in the UK population alone: SNP C+1. For this SNP, 24.5% of the cases were carriers of the G allele, whereas the G allele was observed in only 17.8% of the controls (genotype test p=0.0228). Six SNPs in Gene 962 reached statistical significance in the combined and the US population alone for both allele and genotype tests: 92.9% of the cases were carriers of the G allele in SNP G 4, whereas the G allele was observed in only 86.4% of the controls (combined: allele test p=0.0487), 37.0% of the cases were carriers of the A allele in SNP G 1, whereas the A allele was observed in only 27.2% of the controls (combined: allele test p=0.0280, genotype test p=0.0472), 85.6% of the cases were carriers of the C allele in SNP G 6, whereas the C allele was observed in only 78.3% of the controls (UK: genotype test p=0.0239), 50.0% of the cases were carriers of the A allele in SNP P−2, whereas the A allele was observed in only 22.4% of the controls (US: allele test p=0.0130, genotype test p=0.0116), 45.5% of the cases were carriers of the A allele in SNP Q−1, whereas the A allele was observed in only 21.7% of the controls (US: allele test p=0.0309, genotype test p=0.0261) and 45.8% of the cases were carriers of the T allele in SNP U 2, whereas the T allele was observed in only 21.7% of the controls (US: allele test p=0.0201 and genotype test p=0.0233).  
     [0366] d. Specific IgE: The analyses were performed using asthmatic children with elevated specific IgE levels for at least one allergen, as described in the Linkage Analysis section (Example 3). First, sibling pairs were identified where both sibs were affected and satisfied this new criterion. Of these pairs, one sib was included in the case/control analyses if they showed evidence of linkage at the gene of interest. This phenotype was more restrictive than the Asthma yes/no criteria; hence the number of cases included in the analyses was reduced by approximately 38%.  
     [0367] Frequencies and p-values for all typed SNPs are shown in Tables 18, 19 and 20 or the combined population and for the UK and US populations, separately.  
               TABLE 18                          ASSOCIATION ANALYSIS OF SPECIFIC IgE       PHENOTYPE COMBINED US/UK POPULATION       Combined US &amp; UK                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   14.8%   216   10.2%   59   0.2296   0.3695       845_R_−1   T   28.7%   214   24.2%   60   0.3572   0.5546       845_P_+1   T   6.5%   217   14.2%   60   0.0126   0.0172       845_K_1   T   0.2%   210   0.0%   57   1.0000   1.0000       845_K_−2   A   28.9%   216   24.6%   57   0.4121   0.6113       845_J_1   G   34.5%   210   43.3%   60   0.0856   0.1956       845_J_−1   C   37.1%   217   32.5%   60   0.3910   0.5375       845_I_−1   C   12.8%   191   11.7%   60   0.8746   1.0000       845_H_+1   G   19.6%   217   13.3%   60   0.1414   0.2742       845_H_−1   T   45.2%   217   40.7%   59   0.4045   0.7192       845_G_+1   T   13.2%   216   14.2%   60   0.7635   0.8468       845_F_+1   T   18.4%   215   19.2%   60   0.8944   0.8931       845_D_1   T   0.2%   216   0.9%   57   0.3743   0.3746       845_D_−1   T   9.9%   217   15.8%   57   0.0931   0.0646       847_K_1   A   4.9%   214   4.3%   58   1.0000   1.0000       847_J_+1   T   4.9%   216   1.6%   64   0.1282   0.1200       847_E_+1   C   12.6%   210   15.1%   63   0.4567   0.3427       847_D_−1   C   16.9%   210   17.6%   54   0.8861   0.6933       847_C_+1   G   17.9%   209   21.4%   63   0.4345   0.1027       847_A_2   T   6.7%   217   7.8%   64   0.6925   0.6816       847_A_1   A   1.0%   192   0.8%   60   1.0000   1.0000       874_R_+1   T   39.9%   202   32.5%   60   0.1645   0.3165       874_S_+1   A   39.5%   214   41.4%   64   0.7578   0.8934       874_T_−1   T   48.6%   213   49.2%   65   0.9204   0.8841       874_V_−1   G   17.6%   216   18.5%   65   0.7951   0.5295       803_K_3   T   0.9%   218   0.8%   67   1.0000   1.0000       803_K_2   A   0.2%   217   1.5%   67   0.1402   0.1397       803_I_1   G   28.2%   195   27.3%   66   0.9108   0.6849       803_I_−1   C   0.2%   217   0.0%   64   1.0000   1.0000       803_H_+1   A   25.2%   218   25.8%   66   0.9094   0.8564       803_E_+2   A   44.2%   208   44.6%   65   1.0000   0.9816       962_E_3   C   35.6%   212   33.1%   65   0.6744   0.4216       962_E_+2   C   12.7%   217   8.7%   69   0.2273   0.2212       962_G_4   A   13.6%   202   7.7%   65   0.0891   0.0249       962_G_1   A   27.2%   217   37.7%   69   0.0245   0.0218       962_G_2   A   7.6%   217   8.1%   68   0.8546   0.3300       962_G_6   T   20.4%   194   18.2%   66   0.6158   0.5068       962_H_+2   A   41.5%   217   35.3%   68   0.2288   0.2945       962_M_+2   C   12.7%   213   6.2%   65   0.0389   0.0079       962_P_−2   A   23.8%   214   28.0%   66   0.3568   0.4360       962_Q_−1   A   23.7%   215   28.1%   64   0.3505   0.4884       962_S_−1   C   11.4%   215   3.7%   68   0.0068   0.0046       962_U_1   A   3.0%   214   4.6%   65   0.4086   0.4012       962_U_2   T   23.8%   212   25.4%   67   0.7291   0.8795       962_V_−1   T   34.8%   187   31.1%   66   0.4560   0.5715       962_V_+2   A   4.5%   209   3.7%   68   0.8108   1.0000       962_Z_1   T   31.9%   216   28.3%   69   0.4601   0.2792                  
 
     [0368]               TABLE 19                          ASSOCIATION ANALYSIS OF SPECIFIC IgE       PHENOTYPE UK POPULATION       UK population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   13.6%   140   11.6%   43   0.7179   0.8612       845_R_−1   T   26.6%   137   22.7%   44   0.4875   0.8214       845_P_+1   T   6.4%   140   12.5%   44   0.0724   0.0938       845_K_1   T   0.4%   135   0.0%   41   1.0000   1.0000       845_K_−2   A   27.0%   139   23.3%   43   0.5747   0.8190       845_J_1   G   36.6%   134   43.2%   44   0.3119   0.5431       845_J_−1   C   37.5%   140   34.1%   44   0.6131   0.7816       845_I_−1   C   12.6%   127   11.4%   44   0.8520   1.0000       845_H_+1   G   19.3%   140   13.6%   44   0.2667   0.4230       845_H_−1   T   43.6%   140   38.6%   44   0.4590   0.4785       845_G_+1   T   13.2%   140   15.9%   44   0.5956   0.7510       845_F_+1   T   18.8%   138   20.5%   44   0.7570   0.8585       845_D_1   T   0.0%   140   1.2%   43   0.2350   0.2350       845_D_−1   T   9.3%   140   15.1%   43   0.1601   0.1350       847_K_1   A   3.6%   139   2.5%   40   1.0000   1.0000       847_J_+1   T   2.9%   139   1.1%   46   0.4610   0.4549       847_E_+1   C   12.8%   133   18.9%   45   0.1653   0.0766       847_D_−1   C   16.5%   136   23.1%   39   0.1853   0.1186       847_C_+1   G   17.8%   132   26.1%   46   0.0964   0.0143       847_A_2   T   5.4%   140   6.5%   46   0.6132   0.7884       847_A_1   A   1.3%   120   1.1%   46   1.0000   1.0000       874_R_+1   T   41.5%   129   32.3%   48   0.1412   0.2670       874_S_+1   A   38.0%   137   40.2%   51   0.7215   0.9056       874_T_−1   T   48.9%   136   51.0%   52   0.7309   0.9130       874_V_−1   G   16.9%   139   18.3%   52   0.7623   0.6537       803_K_3   T   1.1%   140   0.9%   53   1.0000   1.0000       803_K_2   A   0.4%   139   0.9%   53   0.4764   0.4769       803_I_1   G   28.6%   117   24.0%   52   0.4281   0.5565       803_I_−1   C   0.4%   139   0.0%   50   1.0000   1.0000       803_H_+1   A   25.7%   140   26.0%   52   1.0000   0.8447       803_E_+2   A   42.4%   132   48.0%   51   0.3491   0.5519       962_E_3   C   36.8%   136   30.0%   50   0.2697   0.3867       962_E_+2   C   12.5%   140   8.5%   53   0.3692   0.3657       962_G_4   A   14.0%   132   8.2%   49   0.1539   0.0449       962_G_1   A   25.2%   139   34.9%   53   0.0742   0.0681       962_G_2   A   6.4%   140   8.7%   52   0.5009   0.3792       962_G_6   T   21.7%   129   15.0%   50   0.1841   0.1382       962_H_+2   A   43.6%   140   36.5%   52   0.2445   0.2880       962_M_+2   C   12.4%   137   3.0%   50   0.0056   0.0165       962_P_−2   A   24.6%   136   24.0%   52   1.0000   1.0000       962_Q_−1   A   24.8%   139   24.5%   49   1.0000   0.9376       962_S_−1   C   10.9%   137   1.0%   52   0.0006   0.0025       962_U_1   A   3.7%   136   4.9%   51   0.5642   0.5575       962_U_2   T   25.0%   136   20.6%   51   0.4151   0.7659       962_V_−1   T   34.4%   122   29.4%   51   0.3829   0.1817       962_V_+2   A   4.5%   134   3.8%   52   1.0000   1.0000       962_Z_1   T   30.0%   140   32.1%   53   0.7114   0.1780                    
     [0369]               TABLE 20                          ASSOCIATION ANALYSIS OF SPECIFIC IgE       PHENOTYPE US POPULATION       US population                                     FREQUENCIES       ALLELE   GENOTYPE                                             GENE_EXON   ALLELE   CNTL   N   CASE   N   P-VALUE   P-VALUE                                                     845_R_1   A   17.1%   76   6.3%   16   0.1750   0.3956       845_R_−1   T   32.5%   77   28.1%   16   0.6822   0.7490       845_P_+1   T   6.5%   77   18.8%   16   0.0362   0.0814       845_K_1   T   0.0%   75   0.0%   16   1.0000   1.0000       845_K_−2   A   32.5%   77   28.6%   14   0.8264   0.7366       845_J_1   G   30.9%   76   43.8%   16   0.2144   0.3882       845_J_−1   C   36.4%   77   28.1%   16   0.4212   0.6502       845_I_−1   C   13.3%   64   12.5%   16   1.0000   0.8344       845_H_+1   G   20.1%   77   12.5%   16   0.4562   0.5019       845_H_−1   T   48.1%   77   46.7%   15   1.0000   0.4033       845_G_+1   T   13.2%   76   9.4%   16   0.7705   1.0000       845_F_+1   T   17.5%   77   15.6%   16   1.0000   0.8876       845_D_1   T   0.7%   76   0.0%   14   1.0000   1.0000       845_D_−1   T   11.0%   77   17.9%   14   0.3432   0.2166       847_K_1   A   7.3%   75   8.3%   18   0.7364   1.0000       847_J_+1   T   8.4%   77   2.8%   18   0.4757   0.2939       847_E_+1   C   12.3%   77   5.6%   18   0.3765   0.3445       847_D_−1   C   17.6%   74   3.3%   15   0.0516   0.1501       847_C_+1   G   18.2%   77   8.8%   17   0.2134   0.5739       847_A_2   T   9.1%   77   11.1%   18   0.7523   0.7410       847_A_1   A   0.7%   72   0.0%   14   1.0000   1.0000       874_R_+1   T   37.0%   73   33.3%   12   0.8215   1.0000       874_S_+1   A   42.2%   77   46.2%   13   0.8308   0.7845       874_T_−1   T   48.1%   77   42.3%   13   0.6733   0.8501       874_V_−1   G   18.8%   77   19.2%   13   1.0000   0.8434       803_K_3   T   0.6%   78   0.0%   14   1.0000   1.0000       803_K_2   A   0.0%   78   3.6%   14   0.1522   0.1522       803_I_1   G   27.6%   78   39.3%   14   0.2596   0.3122       803_I_−1   C   0.0%   78   0.0%   14   1.0000   1.0000       803_H_+1   A   24.4%   78   25.0%   14   1.0000   1.0000       803_E_+2   A   47.4%   76   32.1%   14   0.1529   0.3421       962_E_3   C   33.6%   76   43.3%   15   0.3050   0.3833       962_E_+2   C   13.0%   77   9.4%   16   0.7706   0.7526       962_G_4   A   12.9%   70   6.3%   16   0.3748   0.5960       962_G_1   A   30.8%   78   46.9%   16   0.0999   0.1238       962_G_2   A   9.7%   77   6.3%   16   0.7414   0.7273       962_G_6   T   17.7%   65   28.1%   16   0.2160   0.3921       962_H_+2   A   37.7%   77   31.3%   16   0.5501   0.8134       962_M_+2   C   13.2%   76   16.7%   15   0.5704   0.1201       962_P_−2   A   22.4%   78   42.9%   14   0.0329   0.0244       962_Q_−1   A   21.7%   76   40.0%   15   0.0398   0.0619       962_S_−1   C   12.2%   78   12.5%   16   1.0000   0.4985       962_U_1   A   1.9%   78   3.6%   14   0.4864   0.4895       962_U_2   T   21.7%   76   40.6%   16   0.0411   0.0456       962_V_−1   T   35.4%   65   36.7%   15   1.0000   0.4874       962_V_+2   A   4.7%   75   3.1%   16   1.0000   1.0000       962_Z_1   T   35.5%   76   15.6%   16   0.0362   0.0826                    
     [0370] For the specific IgE phenotype, a single SNP in Gene 845 reached statistical significance in the combined and the US population alone for both the allele and the genotype tests: SNP P+1. For this SNP, 14.2% of the cases in the combined population were carriers of the T allele, whereas the T allele was observed in only 6.5% of the controls (combined:  
     [0371] allele test p=0.0126, genotype test p=0.0172; US: allele test p=0.0362). A single SNP in Gene 847 reached statistical significance in the UK population alone: SNP C+1. For this SNP, 26.1% of the cases were carriers of the G allele, whereas the G allele was observed in only 17.8% of the controls (UK: genotype test p=0.0143). Eight SNPs in Gene 962 reached statistical significance in the combined, the UK population alone and the US population alone for the allele and the genotype tests: 92.3% of the cases in the combined population were carriers of the G allele in SNP G 4, whereas the G allele was observed in only 86.4% of the controls (combined: genotype test p=0.0249; UK: genotype test p=0.0449), 37.7% of the cases were carriers of the A allele in SNP G 1, whereas the A allele was observed in only 27.2% of the controls (combined: allele p=0.0245, genotype p=0.0218), 93.8% of the cases in the combined population were carriers of the G allele in SNP M+2, whereas the G allele was observed in only 87.3% of the controls (combined: allele test p=0.0389, genotype test p=0.0079; UK: allele test p=0.0056, genotype test p=0.0165), 42.9% of the cases were carriers of the A allele in SNP P−2, whereas the A allele was observed in only 22.4% of the controls (US: allele test p=0.0329, genotype test p=0.0244), 40.0% of the cases were carriers of the A allele in SNP Q−1, whereas the A allele was observed in only 21.7% of the controls (US: allele test p=0.0398), 96.3% of the cases in the combined population were carriers of the G allele in SNP S−1, whereas the G allele was observed in only 88.6% of the controls (combined: allele test p=0.0068, genotype test p=0.0046; UK: allele test p=0.0006, genotype test p=0.0025), 40.6% of the cases were carriers of the T allele in SNP U 2, whereas the T allele was observed in only 21.7% of the controls (US: allele p=0.0411, genotype p=0.0456) and 84.4% of the cases were carriers of the C allele in SNP Z 1, whereas the C allele was observed in only 64.5% of the controls (US: allele test p=0.0362).  
     [0372] 3. Association Test with SNP Combinations:  
     [0373] In addition to the analysis of individual SNPs, haplotype frequencies between the case and control groups were also compared. The haplotypes were constructed using a maximum likelihood approach. Existing software for predicting haplotypes was unable to utilize individuals with missing data. Accordingly, a program was developed to make use of all individuals. This allowed more accurate estimates of haplotype frequency. Haplotype analysis based on multiple SNPs in a gene was expected to provide increased evidence for an association between a given phenotype and that gene, if all haplotyped SNPs were involved in the characterization of the phenotype. Otherwise, allelic variation involving those haplotyped SNPs would not be associated more significantly with different risks or susceptibilities toward the phenotype.  
     [0374] a. Asthma Phenotype:  
     [0375] The estimated frequencies of each haplotype for cases and controls were compared using a permutation test. An overall comparison of the distribution of all haplotypes between the two groups was also performed. In Tables 21, 22 and 23 the haplotype analysis (2-at-a-time) is presented for the combined, the UK and the US populations, respectively. The diagonal entries represent the single SNP p-values, while the other entries are the p-values for a test of association between the asthma phenotype and the haplotypes defined by the 2 SNPs listed on the horizontal and vertical axes. The frequencies of the individual SNPs in the cases and controls are shown at the bottom of the tables. Colored cells indicate p-values that were statistically significant (light gray: 0.01 to 0.05, dark gray: 0.001 to 0.0099, black: &lt;0.001). We highlight those combinations that are significant at the 0.05 level and that are more significant than the two tests involving each of the constituent SNPs alone (diagonal entries). One SNP combination in Gene 845 is significant in the US population: SNPs R 1 &amp; K−2 (p=0.0443). Four SNP combinations in Gene 803 are significant in the US population: SNPs K 3 &amp; K 2 (p=0.0409), SNPs K 2 &amp; I 1 (p=0.0146), SNPs K 2 &amp; I−1 (p=0.0383), SNPs K 2 &amp; E+2 (p=0.0197). Thirteen SNP combinations in Gene 962 are significant in the combined, the UK and the US population alone: SNPs E+2 &amp; V−1 (UK p=0.0362), SNPs G 4 &amp; G 1 (combined p=0.0472), SNPs G 4 &amp; P−2 (US p=0.0174), SNPs G 4 &amp; Q−1 (US p=0.016), SNPs G 4 &amp; U 2 (US p=0.013) SNPs G 4 &amp; V+2 (US p=0.0188), SNPs G 1 &amp; G 6 (UK p=0.0369), SNPs G 1 &amp; Q−1 (combined p=0.0441; US p=0.0197), SNPs G 1 &amp; U 2 (US p=0.016), SNPs G 1 &amp; V−1 (combined p=0.0311), SNPs G 6 &amp; S−1 (UK p=0.038), SNPs H+2 &amp; S−1 (combined p=0.0492) and SNPs U 2 &amp; V+2 (US p=0.0212).  
               TABLE 21                       HAPLOTYPE ANALYSIS OF ASTHMA PHENOTYPE COMBINED US/UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_l_−1′   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.4634   0.4245   0.3666   0.619   0.2116   0.5313   0.555   0.6457   0.3764   0.7213   0.6732   0.6692   0.3245   0.7027   845_R_1       R_1       845 —     —   0.507   0.387   0.665   0.1628   0.2303   0.721   0.8127   0.1361   0.17   0.846   0.8137   0.5012   0.6587   845_R_−1       R_−1       845 —     —   —   0.1998   0.3458   0.2262   0.646   0.6124   0.3427   0.1955   0.5843   0.4044   0.4398   0.2971   0.5948   845_P_+1       P_+1       845 —     —   —   —   1   0.3967   0.5143   0.8472   0.7931   0.2278   0.9613   0.8108   0.9055   0.4205   0.7815   845_K_1       K_1       845 —     —   —   —   —   0.2103   0.3312   0.4067   0.2975   0.0555   0.1066   0.438   0.33   0.2143   0.4   845_K_−2       K_−2       845 —     —   —   —   —   —   0.3296   0.2547   0.3243   0.3114   0.6043   0.4215   0.6475   0.2175   0.3693   845_J_1       J_1       845 —     —   —   —   —   —   —   0.794   0.89   0.0977   0.4639   0.8126   0.9791   0.5486   0.8222   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   0.6962   0.2455   0.8919   0.5241   0.4525   0.5393   0.3813   845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   0.1559   0.3291   0.356   0.5486   0.1114   0.3007   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.865   0.9607   0.8998   0.6117   0.9736   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.8053   0.5316   0.5733   0.5129   845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   0.913   0.5852   0.8162   845_F_+1       F_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   0.2339   0.5455   845_D_1       D_1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   —   0.6727   845_D_−1       D_−1       CNTL   14.8%   28.7%   6.5%   0.2%   28.9%   34.5%   37.1%   12.8%   19.6%   45.2%   13.2%   18.4%   0.2%    9.9%   CNTL       CASE   12.5%   26.0%   9.5%   0.0%   24.0%   38.8%   38.5%   11.5%   14.9%   44.2%   13.9%   17.6%   1.0%   11.1%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.6976   0.2577   0.5741   0.8309   0.6644   0.5754   0.6198   847_K_1           847_J_+1   —   0.1394   0.2436   0.263   0.2015   0.2544   0.2522   847_J_+1           847_E_+1   —   —   0.9001   0.3793   0.7355   0.9908   0.8391   847_E_+1           847_D_−1   —   —   —   0.7272   0.6646   0.9053   0.816   847_D_−1           847_C_+1   —   —   —   —   0.3932   0.8445   0.6336   847_C_+1           847_A_2   —   —   —   —   —   0.7457   0.6891   847_A_2           847_A_1   —   —   —   —   —   —   0.6625   847_A_1           CNTL   4.9%   4.9%   12.6%   16.9%   17.9%   6.7%   1.0%   CNTL           CASE   5.7%   2.3%   13.1%   18.3%   20.8%   7.3%   0.5%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.3645   0.6882   0.7952   0.5905   874_R_+1           874_S_+1   —   0.5993   0.3209   0.9142   874_S_+1           874_T_−1   —   —   0.7971   0.8707   874_T_−1           874_V_−1   —   —   —   0.5803   874_V_−1           CNTL   39.9%   39.5%   48.6%   17.6%   CNTL           CASE   35.6%   41.9%   50.0%   19.5%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_1_−1   803_H_+1   803_E_+2                                                                 803_K_3   0.7046   0.104   0.7655   0.9881   0.905   0.9005   803_K_3           803_K_2   —                         0.074                         0.1057   0.1142   803_K_2           803_I_1   —   —   0.7829   0.82   0.835   0.5279   803_I_1           803_I_−1   —   —   —   1   0.9137   0.8473   803_I_−1           803_H_+1   —   —   —   —   0.8524   0.7543   803_H_+1           803_E_+2   —   —   —   —   —   0.806   803_E_+2           CNTL   0.9%   0.2%   28.2%   0.2%   25.2%   44.2%   CNTL           CASE   1.2%   2.1%   26.9%   0.0%   24.4%   45.3%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.4455   0.2588   0.4189   0.0937   0.6231   0.7666   0.6764   0.5219   0.8744   0.8667   0.3369   0.8593   962_E_3       962_E_+2   —   0.4558   0.4429   0.2074   0.6609   0.6666   0.774   0.4971   0.3414   0.4857   0.3437   0.81   962_E_+2       962_G_4   —   —   0.1641                         0.3472   0.4503   0.4306   0.1435   0.4478   0.4527   0.0606   0.4802   962_G_4       962_G_1   —   —   —   0.0541   0.3005   0.0609   0.1946   0.1569   0.0625                         0.0992   0.2891   962_G_1       962_G_2   —   —   —       1   0.863   0.9481   0.6477   0.9326   0.9491   0.3253   0.2915   962_G_2       962_G_6       —   —   —       0.4632   0.8269   0.3438   0.6522   0.6812   0.19   0.0953   962_G_6       962_H_+2       —   —   —           0.6236   0.2445   0.9325   0.8592                         0.9522   962_H_+2       962_M_+2       —   —   —   —           0.2455   0.439   0.4377   0.4435   0.4248   962_M_+2       962_P_−2       —   —       —               0.7026   0.9337   0.3309   0.8719   962_P_+2       962_Q_−1       —   —       —                   0.6345   0.3378   0.9307   962_Q_−1       962_S_−1   —   —   —   —   —   —   —               0.1388   0.2844   962_S_−1       962_U_1   —   —   —   —   —                   —       0.8173   962_U_1       962_U_2           —   —   —           —   —   —   —       962_U_2       962_V_−1           —   —   —               —       —       962_V_−1       962_V_+2   —   —   —   —   —           —   —       —       962_V_+2       962_Z_1   —       —   —   —       —       —   —   —   —   962_Z_1       CNTL   35.6%   12.7%   13.6%   27.2%   7.6%   20.4%   41.5%   12.7%   23.8%   23.7%   11.4%   3.0%   CNTL       CASE   38.7%   10.4%    9.6%   34.3%   7.6%   17.8%   39.5%    9.3%   25.4%   25.7%    7.6%   3.5%   CASE                                                     962_U_2   962_V_−1   962_V_−2   962_Z_1                                             962_E_3   0.8966   0.0994   0.2232   0.7448   962_E_3           962_E_+2   0.4599   0.0563   0.3217   0.6337   962_E_+2           962_G_4   0.4129   0.0772   0.3147   0.2586   962_G_4           962_G_1   0.0902                         0.1532   0.2534   962_G_1           962_G_2   0.7658   0.2209   0.6273   0.9931   962_G_2           962_G_6   0.8694   0.1544   0.3544   0.8695   962_G_6           962_H_+2   0.6692   0.0854   0.2691   0.7072   962_H_+2           962_M_+2   0.3992   0.0824   0.1662   0.6105   962_M_+2           962_P_−2   0.8843   0.2614   0.4837   0.4783   962_P_+2           962_Q_−1   0.8431   0.2369   0.5754   0.5458   962_Q_−1           962_S_−1   0.5332   0.0578   0.1023   0.3447   962_S_−1           962_U_1   0.9205   0.1002   0.3899   0.6979   962_U_1           962_U_2   0.7763   0.112   0.6047   0.9367   962_U_2           962_V_−1                             0.17   0.2122   962_V_−1           962_V_+2   —   —   0.2117   0.3953   962_V_+2           962_Z_1   —           0.797   962_Z_1           CNTL   23.8%   34.8%   4.5%   31.9%   CNTL           CASE   25.0%   26.5%   2.5%   33.1%   CASE                      
 
     [0376]               TABLE 22                       HAPLOTYPE ANALYSIS OF ASTHMA PHENOTYPE UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_1+1   845_F_1+1   845_D_1   845_D_−1                                                                                     845 —     1   0.9397   0.9453   0.9951   0.7734   0.976   0.8431   0.8827   0.4507   0.7585   0.7084   0.7086   0.1635   0.9311   845_R_1       R_1       845 —     —   0.8205   0.9313   0.9699   0.6056   0.2624   0.8569   0.8283   0.5498   0.1328   0.8756   0.9152   0.17   0.9508   845_R_−1       R_−1       845 —     —   —   0.7005   0.9103   0.7895   0.9834   0.8405   0.8749   0.6972   0.932   0.841   0.9488   0.3189   0.6164   845_P_+1       P_+1       845 —     —   —   —   1   0.7384   0.9153   0.7644   0.8366   0.6246   0.9887   0.7308   0.9604   0.0582   0.912   845_K_1       K_1       845 —     —   —   —   —   0.5669   0.7827   0.7547   0.6488   0.434   0.2897   0.7535   0.7374   0.1262   0.7782   845_K_−2       K_−2       845 —     —   —   —   —   —   0.9176   0.6353   0.8137   0.674   0.9811   0.7349   0.9898   0.1654   0.9809   845_J_1       J_1       845 —     —   —   —   —   —   —   0.6126   0.8198   0.2988   0.6821   0.6903   0.9269   0.1298   0.7766   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   0.7575   0.5333   0.9108   0.2364   0.8438   0.1247   0.769   845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   0.4428   0.6175   0.6713   0.8652   0.0632   0.6706   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.9207   0.9052   0.9291   0.1835   0.7567   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.6688   0.4125   0.1321   0.7828   845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   1   0.1697   0.9427   845_F_+1       F_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   0.1275   0.2245   845_D_1       D_−1       845 —     —       —   —   —   —   —   —   —   —   —   —   —   0.7377   845_D_−1       D_−1       CNTL   13.6%   26.6%   6.4%   0.4%   27.0%   36.6%   37.5%   12.6%   19.3%   43.6%   13.2%   18.8%   0.0%    9.3%   CNTL       CASE   13.9%   25.3% 7.3%   0.0%   24.0%   37.5%   40.1%   11.1%   16.1%   42.6%   14.8%   18.3%   1.3%   10.3%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.6053   0.8162   0.4353   0.4016   0.327   0.3663   0.678   847_K_1           847_J_+1   —   1   0.858   0.4861   0.4485   0.8585   0.6844   847_J_+1           847_E_+1   —   —   0.7727   0.1972   0.434   0.8528   0.729   847_E_+1           847_D_−1   —   —   —   0.2351   0.2354   0.6545   0.5647   847_D_−1           847_C_+1   —   —   —   —   0.2175   0.5544   0.5157   847_C_+1           847_A_2   —   —   —   —   —   0.54   0.5849   847_A_2           847_A_1   —   —   —   —   —   —   0.6479   847_A_1           CNTL   3.6%   2.9%   12.8%   16.5%   17.8%   5.4%   1.3%   CNTL           CASE   4.8%   2.3%   14.1%   21.2%   22.9%   7.1%   0.6%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.2918   0.5308   0.7188   0.5775   874_R_+1           874_S_+1   —   0.4122   0.1976   0.5377   874_S_+1           874_T_−1   —   —   0.7645   0.6776   874_T_−1           874_V_−1   —   —   —   0.5164   874_V_−1           CNTL   41.5%   38.0%   48.9%   16.9%   CNTL           CASE   35.8%   42.3%   50.6%   19.6%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   0.6955   0.3719   0.5379   0.9555   0.9532   0.7228   803_K_3           803_K_2   —   0.3124   0.3076   0.3062   0.5566   0.4253   803_K_2           803_I_1   —   —   0.3827   0.5052   0.5243   0.597   803_I_1           803_I_−1   —   —   —   1   0.9649   0.4211   803_I_−1           803_H_+1   —   —   —   —   1   0.5717   803_H_+1           803_E_+2   —   —   —   —   —   0.3903   803_E_+2           CNTL   1.1%   0.4%   28.6%   0.4%   25.7%   42.4%   CNTL           CASE   1.5%   1.5%   24.7%   0.0%   25.3%   46.9%   CASE                                                                                     962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_=2   962_Q_−1   962_S_−1   962_U_1   962_U_2                                                                                 962_E_3   1   0.6202   0.6817   0.1354   0.931   0.6669   0.8392   0.4729   0.8903   0.9042   0.3877   0.6387   0.82   962_E_3       962_E_+2       0.4621   0.409   0.1993   0.4089   0.1655   0.5307   0.3457   0.323   0.423   0.322   0.7633   0.3004   962_E_+2       962_G_4   —       0.3105   0.0711   0.5288   0.2277   0.5171   0.2912   0.4569   0.5166   0.1901   0.6237   0.3428   962_G_4       962_G_1   —       —   0.0502   0.2925                         0.175   0.1113   0.1215   0.1506   0.1123   0.1071   0.1606   962_G_1       962_G_2       —   —   —   0.7106   0.5809   0.7814   0.4259   0.8995   0.9066   0.2037   0.3868   0.5857   962_G_2       962_G_6   —       —   —   —   0.2261   0.4569   0.1416   0.1459   0.1754                         0.0718   0.507   962_G_6       962_H_+2   —       —   —   —   —   0.3926   0.301   0.7112   0.7315   0.1376   0.7039   0.5272   962_H_+2       962_M_+2           —   —   —   —       0.1221   0.2005   0.2046   0.309   0.2791   0.1253   962_M_+2       962_P_−2               —   —       —       0.5757   0.7311   0.21   0.9297   0.891   962_P_−2       962_Q_−1               —   —       —           0.5776   0.2338   0.882   0.8633   962_Q_−1       962_S_−1   —       —       —               —       0.1006   0.2301   0.2779   962_S_−1       962_U_1           —   —   —               —           1   0.7188   962_U_1       962_U_2           —   —       —   —       —   —   —       0.3727   962_U_2       962_V_−1   —       —   —               —   —       —   —       962_V_−1       962_V_+2   —   —   —   —                   —       —   —       962_V_+2       962_Z_1       —   —   —           —       —   x   —   —       962_Z_1       CNTL   36.8%   12.5%   14.0%   25.2%   6.4%   21.7%   43.6%   12.4%   24.6%   24.8%   10.9%   3.7%   25.0%   CNTL       CASE   36.4%    9.9%   10.6%   33.5%   7.4%   16.8%   39.5%    7.8%   22.0%   22.3%    6.3%   3.7%   21.3%   CASE                                                 962_V_−1   962_V_+2   962_Z_1                                                     962_E_3   0.3109   0.5899   0.5887   962_E_3           962_E_+2                         0.4364   0.5318   962_E_+2           962_G_4   0.262   0.2455   0.2256   962_G_4           962_G_1   0.0671   0.2155   0.1322   962_G_1           962_G_2   0.4558   0.6792   0.7051   962_G_2           962_G_6   0.0978   0.2839   0.3739   962_G_6           962_H_+2   0.3122   0.2422   0.5073   962_H_+2           962_M_+2   0.1441   0.1237   0.1854   962_M_+2           962_P_−2   0.1815   0.515   0.5684   962_P_−2           962_Q_−1   0.2645   0.724   0.5896   962_Q_−1           962_S_−1   0.1283   0.0951   0.0898   962_S_−1           962_U_1   0.2327   0.6153   0.5005   962_U_1           962_U_2   0.1   0.6232   0.734   962_U_2           962_V_−1   0.1154   0.2506   0.5107   962_V_−1           962_V_+2       0.4526   0.3607   962_V_+2           962_Z_1   —   0.2713   962_Z_1           CNTL   34.4%   4.5%   30.0%   CNTL           CASE   27.2%   2.6%   35.1%   CASE                        
     [0377]               TABLE 23                       HAPLOTYPE ANALYSIS OF ASTHMA PHENOTYPE US POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.1433   0.0751   0.0677   0.0985                         0.1403   0.2377   0.2748   0.3446   0.1361   0.3212   0.3334   0.236   0.289   845_R_1       R_1       845 —         0.718   0.1286   0.6516   0.3598   0.3854   0.5459   0.9798   0.1447   0.7334   0.9033   0.9244   0.6754   0.7863   845_R_−1       R_−1       845 —         —                                               0.0855   0.1031   0.1415   0.0766   0.0661   0.1272                         0.1122   0.0741   0.1412   845_P_+1       P_+1       845 —     —   —   —   1   0.2461   0.1405   0.6341   0.9495   0.1157   0.8569   0.6691   0.7337   0.8977   0.5857   845_K_1       K_−1       845 —     —   —   —   —   0.3465   0.2259   0.3114   0.574   0.0596   0.3323   0.5334   0.4471   0.406   0.524   845_K_−2       K_−2       845 —     —   —   —   —   —   0.1542   0.2328   0.2346   0.1707   0.2033   0.2717   0.3959   0.282   0.2671   845_J_1       J_1       845 —     —   —   —   —   —   —   0.7267   0.8971   0.2452   0.5322   0.7891   0.9281   0.7726   0.7919   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   1   0.4022   0.9652   0.9853   0.6398   0.9932   0.6283   845_I_−1       1_−1       845 —     —   —   —   —   —   —   —   —   0.1915   0.2811   0.3217   0.5231   0.3226   0.3268   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.8652   0.9207   0.933   0.9655   0.7683   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.8037   0.9146   0.7918   0.4422   845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   0.8253   0.836   0.698   845_F_+1       F_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   1   0.6294   845_D_1       D_1       845 —     —       —   —   —   —   —   —   —   —   —   —   —   0.5906   845_D_−1       D_−1       CNTL   17.1%   32.5%    6.5%   0.0%   32.5%   30.9%   36.4%   13.3%   20.1%   48.1%   13.2%   17.5%   0.7%   11.0%   CNTL       CASE    7.1%   28.3%   17.4%   0.0%   23.8%   43.5%   32.6%   13.0%   10.9%   50.0%   10.9%   15.2%   0.0%   14.3%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.7617   0.3082   0.8693   0.2469   0.7319   0.9941   0.9725   847_K_1           847_J_+1   —   0.1949   0.1683   0.0636   0.1634   0.0917   0.1948   847_J_+1           847_E_+1   —   —   0.7899   0.6313   0.6794   0.8897   0.6777   847_E_+1           847_D_+1   —   —   —   0.1431   0.4248   0.2657   0.1912   847_D_−1           847_C_+1   —   —   —   —   0.5067   0.8066   0.5641   847_C_+1           847_A_2   —   —   —   —   —   1   0.9553   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   7.3%   8.4%   12.3%   17.6%   18.2%   9.1%   0.7%   CNTL           CASE   8.3%   2.1%    9.1%    7.5%   13.0%   8.3%   0.0%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.8552   0.8248   0.9906   0.9913   874_R_+1           874_S_+1   —   0.862   0.9128   0.9877   874_S_+1           874_T_−1   —   —   1   0.9906   874_T_−1           874_V_−1   —   —   —   1   874_V_−1           CNTL   37.0%   42.2%   48.1%   18.8%   CNTL           CASE   35.0%   40.5%   47.6%   19.1%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   1                         0.3618   0.8151   0.6769   0.5253   803_K_3           803_K_2   —                                                                     0.0581                         803_K_2           803_I_1   —   —   0.2666   0.3065   0.5303   0.4402   803_I_1           803_I_−1   —   —   —   1   0.6784   0.3286   803_I_−1           803_H_+1   —   —   —   —   0.6895   0.4468   803_H_+1           803_E_+2   —   —   —   —   —   0.3902   803_E_+2           CNTL   0.6%   0.0%   27.6%   0.0%   24.4%   47.4%   CNTL           CASE   0.0%   4.5%   36.4%   0.0%   20.5%   38.6%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   296_M_+2   296_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.0842   0.116   0.0783   0.0837   0.2803   0.3026   0.2041   0.3918   0.0681   0.0605   0.3617   0.1492   962_E_3       962_E_+2       1   0.5883   0.8796   0.9873   0.6633   0.9931   0.9613   0.1674   0.1752   0.9814   0.9603   962_E_+2       962_G_4           0.291   0.1488   0.5145   0.5225   0.6364   0.2885                                               0.2983   0.4429   962_G_4       962_G_1               0.3839   0.8397   0.7321   0.4268   0.7269   0.0502                         0.587   0.5489   962_G_1       962_G_2                   1   0.9314   0.9849   0.954   0.0577 
                 
   0.9935   0.8216   962_G_2       962_G_6                       0.5195   0.946   0.9703   0.1488   0.1326   0.8997   0.8463   962_G_6       962_H_+2                           0.8654   0.6608   0.2227   0.1321   0.4193   0.8572   962_H_+2       962_M_+2           —           —       0.8065   0.0529   0.059   0.1433   0.8703   962_M_+2       962_P_+2       —       —       —   —   —                         0.0864   0.0605   0.1057   962_P_−2       962_Q_−1   —   —   —   —       —   —   —   —                         0.0651   0.0846   962_Q_−1       962_S_−1       —           —   —   —   —   —       1   0.9244   962_S_−1       962_U_1                       —   —   —   —   —       1   962_U_1       962_U_2       —               —   —   —   —   —           962_V_2       962_V_−1           —           —   —   —   —   —       —   962_V_−1       962_V_+2                   —   —   —   —   —   —           962_V_+2       962_Z_1       —           —   —   —   —   —   —           962_Z_1       CNTL   33.6%   13.0%   129%   30.8%   9.7%   17.7%   37.7%   13.2%   22.4%   21.7%   12.2%   1.9%   CNTL       CASE   47.8%   12.5%    6.3%   37.5%   8.3%   21.7%   39.6%   15.2%   40.5%   39.1%   12.5%   2.4%   CASE                                                     962_U_2   962_V_−1   962_V_+2   296_Z_1                                                         962_E_3                         0.2377   0.2088   0.1554   962_E_3           962_E_+2   0.1617   0.6046   0.8233   0.5705   962_E_+2           962_G_4                         0.2715                         0.2321   962_G_4           962_G_1                         0.3085   0.3786   0.2794   962_G_1           962_G_2                         0.2836   0.432   0.4668   962_G_2           962_G_6   0.1362   0.3672   0.599   0.6065   962_G_6           962_H_+2   0.1034   0.2646   0.7828   0.5467   962_H_+2           962_M_+2   0.056   0.5608   0.7893   0.5495   962_M_+2           962_P_+2   0.0849   0.1147                         0.0938   962_P_−2           962_Q_−1                         0.0563                         0.0875   962_Q_−1           962_S_−1   0.0551   0.5854   0.8282   0.7192   962_S_−1           962_U_1   0.064   0.5148   0.6903   0.5005   962_U_1           962_U_2                                                                     0.0587   962_V_2           962_V_−1       0.1995   0.0821   0.076   962_V_−1           962_V_+2   —       0.6823   0.2958   962_V_+2           962_Z_1               0.2185   962_Z_1           CNTL   21.7%   35.4%   4.7%   35.5%   CNTL           CASE   39.6%   23.9%   2.1%   25.0%   CASE                        
     [0378] All SNP combinations in Tables 21, 22, and 23 that demonstrated a significant difference (p≦0.05) in the distribution of frequencies of the four haplotypes between the cases and the control populations were further analyzed to identify individual haplotypes that were also significant. Table 24 presents the haplotypes that were significantly associated, at the 0.05 level of significance, with the asthma phenotype. Haplotypes with higher allele frequency in the case population than in the control population acted as risk factors that increased the susceptibility to asthma. Haplotypes with lower allele frequencies in the case population than in the control population acted as protective factors that decreased the susceptibility to asthma. For Gene 962, three haplotypes involving allele A at SNP G1 were susceptibility haplotypes, associated with an increased risk of asthma at the 0.05 level of significance in the combined population. They were haplotypes A/A (SNPs G1/Q−1, p=0.0084), A/C (SNPs G1/V−1, p=0.0142) and G/A (SNPs G4/G1, p=0.045). Haplotype A/C was a protective haplotype (SNPs H+2/S−1, p=0.0097). In the UK population, three haplotypes were protective. They were haplotypes C/T (SNPs E+2/V−1, p=0.0149), G/T (SNPs G1/G6, p=0.0164) and C/C (SNPs G6/S−1, p=0.0308). In the US population, six haplotypes were susceptibility haplotypes. They were G/A (SNPs G4/Q-1, p=0.0466), G/T (SNPs G4/U2, p=0.0363), A/A (SNPs G4/V+2, p=0.0428), A/A (SNPs G1/Q−1, p=0.0024), A/T (SNPs G1/U2, p=0.0027) and T/G (SNPs U2/V+2, p=0.0216). For Gene 845, haplotype G/G (SNPs R1/K−2, p=0.01 16) was a susceptibility haplotype in the US population and haplotype A/G (SNPs R1/K−2, p=0.0367) was protective in the US population. For Gene 803, three haplotypes involving allele A at SNP K2 were susceptibility haplotypes in the US population. They were haplotypes C/A (SNPs K3/K2, p=0.0451), A/C (SNPs K2/I1, p=0.0453) and A/A (SNPs K2/E+2, p=0.0442).  
                                   TABLE 24                           SNP                           COMBI-   HAPLO-   FREQUENCIES       P-       GENE   NATION   TYPE   CNTL   CASE   VALUE                                    Asthma Yes/No       Combined US and UK                                     962   G4/G1   GA   0.208523   0.278141   0.045       962   G1/Q−1   AA   0.049187   0.12121   0.0084       962   G1/V−1   AC   0.157636   0.256126   0.0142       962   H+2/S−1   AC   0.05552   0.000001   0.0097                 Asthma Yes/No       UK Population                                     962   E+2/V−1   CT   0.054678   0   0.0149       962   G1/G6   GT   0.198435   0.099309   0.0164       962   G6/S−1   CC   0.101659   0.040006   0.0308                 Asthma Yes/No       US Population                                     845   R1/K−2   GG   0.504855   0.731782   0.0116       845   R1/K−2   AG   0.17047   0.032411   0.0367       803   K3/K2   CA   0   0.045455   0.0451       803   K2/I−1   AG   0   0.045455   0.0478       803   K2/E+2   AA   0   0.045455   0.0442       962   G4/Q−1   GA   0.192645   0.327035   0.0466       962   G4/U2   GT   0.191643   0.333333   0.0363       962   G4/V+2   AA   0   0.020833   0.0428       962   G1/Q−1   AA   0.042798   0.25136   0.0024       962   G1/U2   AT   0.039558   0.248019   0.0027       962   U2/V+2   TG   0.217236   0.375   0.0216                  
 
     [0379] b. Bronchial Hyper-Responsiveness:  
     [0380] In Tables 25, 26 and 27, the haplotype analysis (2-at-a-time) is presented for the combined, the UK and the US populations, respectively. Ten SNP combinations in Gene 845 are significant in the combined, the UK and the US population alone: SNPs R 1 &amp; K−2 (combined p=0.0385), SNPs R−1 &amp; J 1 (UK p=0.013), SNPs P+1 &amp; H+1 (US p=0.0267), SNPs K 1 &amp; H+1 (US p=0.0076), SNPs K 1 &amp; D−1 (combined p=0.0134), SNPs K−2 &amp; H+1 (combined p=0.0355), SNPs K−2 &amp; D 1 (UK p=0.0428), SNPs J 1 &amp; D 1 (UK p=0.0097), SNPs H−1 &amp; D 1 (UK p=0.0422) and SNPs D 1 &amp; D−1 (UK p=0.007). Nine SNP combinations in Gene 847 are significant in the US population: SNPs K 1 &amp; D−1 (p=0.0118), SNPs K 1 &amp; C+1 (p=0.0225), SNPs J+1 &amp; E+1 (p=0.038), SNPs J+1 &amp; D−1 (p=0.0081), SNPs J+1 &amp; C+1 (p=0.0077), SNPs E+1 &amp; C+1 (p=0.0296), SNPs D−1 &amp; A 2 (p=0.0343), SNPs D−1 &amp; A 1 (p=0.0483) and SNPs C+1 &amp; A 2 (p=0.0328). Two SNP combinations in Gene 803 are significant in the US population: SNPs K 2 &amp; I 1 (p=0.0212), and SNPs K 2 &amp; E+2 (p=0.0281). Two SNP combinations in Gene 962 are significant in the UK and the US population alone: SNPs G 2 &amp; S−1 (UK p=0.0491) and SNPs E 3 &amp; E+2 (US p=0.0431).  
               TABLE 25                       HAPLOTYPE ANALYSIS OF BHR PHENOTYPE COMBINED US/UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.1227   0.093   0.1055   0.254                                               0.3268   0.2586   0.4918   0.0834   0.4205   0.418   0.0775                         845_R_1       R_1       845 —     —   0.4252   0.1888   0.4799   0.1658                         0.1544   0.7499   0.0753   0.1256   0.729   0.7624   0.2879                         845_R_−1       R_−1       845 —     —   —   0.0715   0.1912   0.1045   0.0511   0.3078   0.2192   0.1092   0.184   0.18   0.2121   0.1304   0.0807   845_P_+1       P_+1       845 —         —   —   1   0.2677                         0.4404   0.9403   0.2549   0.3269   0.7194   0.9307   0.2135                         845_K_1       K_1       845 —     —   —   —   —   0.1469                         0.0665   0.2862                         0.2709   0.3012   0.2844   0.1286                         845_K_−2       K_−2       845 —     —   —   —   —   —                                                                                                                                                                                                         845_J_1       J_1       845 —     —   —   —   —   —   —   0.3952   0.5902   0.2621   0.3141   0.8472   0.8055   0.197                         845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   1   0.2429   0.37   0.6965   0.7552   0.584                         845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   0.1325   0.0718   0.2968   0.4653   0.0749                         845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.1969   0.424   0.3396   0.192   0.0636   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.7318   0.6831   0.4852                         845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   1   0.5881                         845_F_+1       F_+1       CNTL   14.8%   28.7%    6.5%   0.2%   28.9%   34.5%   37.1%   12.8%   19.6%   45.2%   13.2%   18.4%   0.2%    9.9%   CNTL       CASE    8.3%   23.8%   12.5%   0.0%   20.9%   50.0%   31.8%   12.5%   12.5%   37.5%   14.8%   18.2%   1.2%   20.2%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.781   0.1716   0.8466   0.7351   0.93   0.6906   0.8334   847_K_1           847_J_+1   —   0.1502   0.1639   0.1579   0.2008   0.1666   0.1498   847_J_+1           847_E_+1   —   —   1   0.8405   0.964   0.3695   0.9439   847_E_+1           847_D_−1   —   —   —   0.7526   0.7406   0.617   0.9136   847_D_−1           847_C_+1   —   —   —   —   1   0.6384   0.9961   847_C_+1           847_A_2   —   —   —   —   —   0.4852   0.7284   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   4.9%   4.9%   12.6%   16.9%   17.9%   6.7%   1.0%   CNTL           CASE   3.6%   1.1%   12.0%   15.1%   17.7%   4.2%   1.0%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.0738   0.1638   0.2993   0.2605   874_R_+1           874_S_+1   —   0.6422   0.3442   0.7898   874_S_+1           874_T_−1   —   —   0.8214   0.92   874_T_−1           874_V_−1   —   —   —   0.7695   874_V_−1           CNTL   39.9%   39.5%   48.6%   17.6%   CNTL           CASE   29.3%   42.6%   46.9%   18.8%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   0.1647   0.3798   0.4488   0.4937   0.3962   0.5099   803_K_3           803_K_2   —   0.3776   0.9758   0.9847   0.5573   0.8898   803_K_2           803_I_1   —   —   1   0.9954   0.7551   0.6129   803_I_1           803_I_−1   —   —   —   1   0.5881   0.7119   803_I_−1           803_H_+1   —   —   —   —   0.5414   0.8006   803_H_+1           803_E_+2   —   —   —   —   —   0.6722   803_E_+2           CNTL   0.9%   0.2%   28.2%   0.2%   25.2%   44.2%   CNTL           CASE   2.6%   0.9%   28.4%   0.0%   21.9%   46.5%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.9071   0.4317   0.516   0.4162   0.9572   0.7189   0.4794   0.6478   0.7666   0.8326   0.774   0.874   962_E_3       962_E_+2       0.3128   0.3279   0.6247   0.2338   0.4261   0.4258   0.3215   0.2481   0.3352   0.2178   0.4443   962_E_+2       962_G_4   —       0.1756   0.2176   0.365   0.3236   0.2693   0.1477   0.3337   0.3724   0.1964   0.3196   962_G_4       962_G_1   —           0.626   0.7488   0.6561   0.6164   0.5051   0.6091   0.4918   0.6264   0.7516   962_G_1       962_G_2                   0.683   0.154   0.7557   0.3427   0.7201   0.7211   0.1784   0.5279   962_G_2       962_G_6   —                   0.3165   0.2217   0.2693   0.0824   0.0752   0.2377   0.1175   962_G_6       962_H_+2   —   —   —       —       0.2641   0.0762   0.622   0.6895   0.1513   0.6198   962_H_+2       962_M_+2                   —   —       0.2968   0.3632   0.3917   0.6844   0.3581   962_M_+2       962_P_−2                   —   —           0.6921   0.9484   0.5977   0.789   962_P_−2       962_Q_−1   —               —   —   —   —   —   0.7901   0.6265   0.7198   962_Q_−1       962_S_−1   —   —           —   —   —   —   —       0.3741   0.4508   962_S_−1       962_U_1   —               —   —   —   —       —       0.3617   962_U_1       962_U_2   —               —   —   —   —       —   —       962_U_2       962_V_−1               —   —   —   —   —       —       —   962_V_−1       962_V_+2   —   —   —       —   —   —   —   —   —       —   962_V_+2       962_Z_1           —   —   —   —   —   —       —       —   962_Z_1       CNTL   35.6%   12.7%   13.6%   27.2%   7.6%   20.4%   41.5%   12.7%   23.8%   23.7%   11.4%   3.0%   CNTL       CASE   34.7%    8.7%    8.3%   29.8%   8.8%   15.3%   35.3%    8.2%   21.4%   21.9%    7.8%   4.9%   CASE                                                     962_U_2   962_V_−1   982_V_+2   962_Z_1                                                         962_E_3   0.7189   0.3361   0.6552   0.6083   962_E_3           962_E_+2   0.3618   0.1028   0.3315   0.3764   962_E_+2           962_G_4   0.2854   0.1625   0.2663   0.2801   962_G_4           962_G_1   0.7442   0.2441   0.6164   0.5673   962_G_1           962_G_2   0.8726   0.4279   0.6058   0.5691   962_G_2           962_G_6   0.6195   0.2712   0.3766   0.3552   962_G_6           962_H_+2   0.5144   0.2246   0.2681   0.4391   962_H_+2           962_M_+2   0.133   0.2053   0.0779   0.4261   962_M_+2           962_P_−2   0.8121   0.2414   0.471   0.5539   962_P_−2           962_Q_−1   0.2688   0.1939   0.5462   0.6022   962_Q_−1           962_S_−1   0.3359   0.2835   0.0991   0.5538   962_S_−1           962_U_1   0.693   0.1535   0.3288   0.5037   962_U_1           962_U_2   0.5095   0.1516   0.4574   0.6757   962_U_2           962_V_−1       0.1476   0.2689   0.2726   962_V_−1           962_V_+2   —       0.3973   0.3009   962_V_+2           962_Z_1   —   —       0.2968   962_Z_1           CNTL   23.8%   34.8%   4.5%   31.9%   CNTL           CASE   20.0%   26.5%   2.0%   37.5%   CASE                      
 
     [0381]               TABLE 26                       HAPLOTYPE ANALYSIS OF BHR PHENOTYPE UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.4358   0.3636   0.4243   0.5414   0.1445   0.0893   0.7328   0.6729   0.8754   0.1964   0.8488   0.8809   0.0859                         845_R_1       R_1       845 —     —   0.4437   0.4676   0.5086   0.094                         0.3194   0.6632   0.3213   0.0654   0.6852   0.6861   0.133                         845_R_−1       R_−1       845 —     —   —   0.212   0.4876   0.2276   0.1577   0.6931   0.5344   0.419   0.3042   0.4678   0.5175   0.1343   0.0725   845_P_+1       P_+1       845 —     —   —       1   0.3021                         0.6043   0.9481   0.4873   0.3001   0.6846   0.9503   0.0978                         845_K_1       K_1       845 —     —   —           0.1299   0.0504   0.1195   0.247   0.1486   0.1872   0.2942   0.2783                                               845_K_−2       K_−2       845 —         —   —                                                                             0.1209   0.0621   0.1018   0.0957                                               845_J_1       J_1       845 —     —   —   —               0.5899   0.7923   0.6445   0.3626   0.9382   0.9304   0.1438                         845_J_−1       J_−1       R_1       845 —         —   —   —   —   —       1   0.6382   0.2665   0.7018   0.9058   0.2428                         845_I_−1       I_−1       845 —             —   —   —   —   —       0.4994   0.1731   0.6698   0.8308   0.0868                         845_H_+1       H_+1       845 —         —   —   —   —       —           0.1454   0.3025   0.2504                                               845_H_−1       H_+1       845 —         —   —   —   —       —   —   —       0.7047   0.8022   0.1862                         845_G_+1       G_+1       845 —         —   —   —   —       —   —       —       1   0.2476                         845_F_+1       F_+1       845 —         —   —   —   —       —   —   —   —           0.2045                         845_D_1       D_1       845 —         —   —   —   —                   —       —                             845_D_−1       D_−1       CNTL   13.6%   26.6%    6.4%   0.4%   27.0%   36.6%   37.5%   12.6%   19.3%   43.6%   13.2%   18.8%   0.0%    9.3%   CNTL       CASE    9.7%   21.4%   10.8%   0.0%   18.1%   51.4%   33.8%   12.2%   14.9%   33.8%   14.9%   18.9%   1.4%   20.8%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.725   0.6597   0.704   0.9645   0.9194   0.9621   0.8974   847_K_1           847_J_+1   —   0.69   0.7023   0.6844   0.5625   0.8319   0.7757   847_J_+1           847_E_+1   —   —   0.8486   0.6266   0.8008   0.6334   0.8728   847_E_+1           847_D_−1   —   —   —   0.7215   0.5405   0.699   0.9003   847_D_−1           847_C_+1   —   —   —       0.513   0.6701   0.8359   847_C_+1           847_A_2   —   —   —   —       1   0.9999   847_A_2           847_A_1   —   —   —   —   —       1   847_A_1           CNTL   3.6%   2.9%   12.8%   16.5%   17.8%   5.4%   1.3%   CNTL           CASE   4.4%   1.3%   14.1%   18.6%   21.3%   5.0%   1.3%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.1116   0.2338   0.3081   0.4057   874_R_+1           874_S_+1   —   0.2947   0.233   0.56   874_S_+1           874_T_−1   —   —   0.8989   0.9168   874_T_−1           874_V_−1   —   —   —   0.7379   874_V_−1           CNTL   41.5%   38.0%   48.9%   16.9%   CNTL           CASE   30.8%   44.9%   47.5%   18.8%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   0.1828   0.4394   0.3288   0.5003   0.3875   0.356   803_K_3           803_K_2       1   0.6552   0.9425   0.5862   0.4151   803_K_2           803_I_1   —   —   0.5933   0.6726   0.4824   0.511   803_I_1           803_I_−1   —   —       1   0.6153   0.4267   803_I_−1           803_H_+1   —   —   —       0.4953   0.487   803_H_+1           803_E_+2   —       —   —       0.2821   803_E_+2           CNTL   1.1%   0.4%   28.6%   0.4%   25.7%   42.4%   CNTL           CASE   3.1%   0.0%   25.5%   0.0%   21.9%   49.0%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.515   0.7464   0.5152   0.3509   0.5785   0.6404   0.4499   0.4264   0.3429   0.4711   0.5547   0.6799   962_E_3       962_E_+2       0.5802   0.5161   0.7985   0.1852   0.6109   0.4938   0.451   0.1519   0.2682   0.3983   0.7012   962_E_+2       962_G_4   —       0.2549   0.2797   0.2378   0.2417   0.3093   0.2107   0.235   0.2861   0.2708   0.3498   962_G_4       962_G_1       —       0.4922   0.531   0.492   0.4817   0.4536   0.4058   0.4423   0.5459   0.432   962_G_1       962_G_2                   0.2444   0.2212   0.4306   0.1508   0.6403   0.6035                         0.4173   962_G_2       962_G_6       —       —       0.354   0.2355   0.2219   0.0881   0.0733   0.1759   0.198   962_G_6       962_H_+2       —   —   —   —       0.1748   0.0984   0.2908   0.4093   0.2204   0.483   962_H_+2       962_M_+2       —               —       0.2352   0.1972   0.2338   0.6025   0.4056   962_M_+2       962_P_−2       —                   —       0.3843   0.7457   0.4412   0.7518   962_P_−2       962_Q_−1       —               —   —   —   —   0.465   0.5054   0.8408   962_Q_−1       962_S_−1       —   —           —   —   —   —       0.3107   0.5315   962_S_−1       962_U_1       —   —   —   —   —   —   —   —   —       0.7524   962_U_1       962_U_2       —               —   —   —   —   —   —       962_U_2       962_V_−1       —               —   —   —   —   —       —   962_V_−1       962_V_+2           —           —   —   —   —       —       962_V_+2       962_Z_1                                   —   —       —   962_Z_1       CNTL   36.8%   12.5%   14.0%   25.2%    6.4%   21.7%   43.6%   12.4%   24.6%   24.8%   10.9%   3.7%   CNTL       CASE   32.1%   10.0%    85%   28.9%   10.2%   16.7%   35.2%    7.1%   19.3%   20.2%    6.8%   4.5%   CASE                                                     962_U_2   962_V_−1   962_V_+2   962_Z_1                                                         962_E_3   0.3051   0.2308   0.7642   0.2543   962_E_3           962_E_+2   0.1706   0.1462   0.6373   0.3188   962_E_+2           962_G_4   0.1569   0.1482   0.4131   0.2011   962_G_4           962_G_1   0.4464   0.1672   0.7516   0.178   962_G_1           962_G_2   0.2471   0.2202   0.5097   0.3565   962_G_2           962_G_6   0.462   0.2207   0.4478   0.1923   962_G_6           962_H_+2   0.1388   0.191   0.2337   0.2066   962_H_+2           962_M_+2   0.0629   0.1486   0.087   0.159   962_M_+2           962_P_−2   0.8329   0.1438   0.4439   0.3371   962_P_−2           962_Q_−1   0.3176   0.1324   0.6132   0.3637   962_Q_−1           962_S_−1   0.1474   0.2006   0.1081   0.2071   962_S_−1           962_U_1   0.5151   0.067   0.5727   0.3179   962_U_1           962_U_2   0.1868   0.0501   0.3777   0.2338   962_U_2           962_V_−1       0.1357   0.3014   0.2074   962_V_−1           962_V_+2   —       0.5311   0.1916   962_V_+2           962_Z_1       —       0.0924   962_Z_1           CNTL   25.0%   34.4%   4.5%   30.0%   CNTL           CASE   17.4%   25.0%   2.3%   40.0%   CASE                        
     [0382]               TABLE 27                       HAPLOTYPE ANALYSIS OF BHR PHENOTYPE US POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_−1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.2168   0.1594   0.0827   0.0855   0.1679   0.2103   0.1745   0.2628   0.1094   0.1574   0.2903   0.2857   0.1568   0.2542   845_R_1       R_1       845 —         0.7742   0.1844   0.9763   0.9421   0.4599   0.4528   0.9788   0.0539   0.9001   0.9422   0.9765   0.9697   0.7545   845_R_−1       R_−1       845 —     —       0.0801   0.0886   0.1795   0.3146   0.1941   0.2962                         0.1209   0.2818   0.3014   0.1605   0.2485   845_P_+1       P_+1       845 —     —       —   1   0.966   0.5089   0.2612   0.928                         0.5848   0.8566   0.8208   0.8841   0.681   845_K_1       K_1       845 —     —   —   —       0.7742   0.4363   0.4784   0.9915   0.0651   0.8203   0.9969   0.9798   0.9669   0.7489   845_K_−2       K_−2       845 —     —   —               0.3787   0.4458   0.6187   0.0897   0.0573   0.744   0.6551   0.4122   0.7182   845_J_1       J_1       845 —     —               —       0.383   0.5758   0.0656   0.2691   0.5926   0.5584   0.394   0.6422   845_J_−1       J_−1       845 —     —               —   —   —   1   0.0879   0.7864   0.8033   0.6122   0.9962   0.5973   845_I_−1       I_−1       845 —     —       —           —   —       0.0752   0.0751   0.0988   0.133   0.0521   0.061   845_H_+1       H_+1       845 —     —           —       —   —   —   —   0.5841   0.7955   0.8275   0.6282   0.5876   845_H_−1       H_−1       845 —             —           —   —               1   0.684   0.9967   0.5614   845_G_+1       G_+1       845 —                 —       —   —   —               1   0.9645   0.6021   845_F_+1       F_+1       845 —     —       —           —   —   —       —   —       1   0.4079   845_D_1       D_1       845 —     —       —   —   —   —   —   —           —   —       0.6307   845_D_−1       D_−1       CNTL   17.1%   32.5%    6.5%   0.0%   32.5%   30.9%   36.4%   13.3%   20.1%   48.1%   13.2%   17.5%   0.7%   11.0%   CNTL       CASE    0.0%   35.7%   21.4%   0.0%   35.7%   42.9%   21.4%   14.3%    0.0%   57.1%   14.3%   14.3%   0.0%   16.7%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.6027   0.1218   0.0756                                               0.0971   0.219   847_K_1           847_J_+1   —   0.6146                                                                     0.0668   0.2001   847_J_+1           847_E_+1   —   —   0.3721   0.11                         0.1021   0.1828   847_E_+1           847_D_−1   —   —   —   0.0779   0.0563                                               847_D_−1           847_C_+1   —   —   —   —   0.077                         0.0514   847_C_+1           847_A_2   —   —   —   —   —   0.3669   0.117   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   7.3%   8.4%   12.3%   17.6%   18.2%   9.1%   0.7%   CNTL           CASE   0.0%   0.0%    0.0%    0.0%    0.0%   0.0%   0.0%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.3818   0.0621   0.4429   0.115   874_R_+1           874_S_+1   —   0.4382   0.2736   0.5583   874_S_+1           874_T_−1   —   —   0.7977   0.9652   874_T_−1           874_V_−1   —   —   —   1   874_V_−1           CNTL   37.0%   42.2%   48.1%   18.8%   CNTL           CASE   21.4%   31.3%   43.8%   18.8%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   1   0.182   0.2121   0.782   0.8147   0.3784   803_K_3           803_K_2   —   0.1034                         0.0804   0.1419                         803_K_2           803_I_1   —   —   0.1714   0.1246   0.3257   0.3586   803_I_1           803_I_−1   —   —   —   1   0.9227   0.2631   803_I_−1           803_H_+1   —   —   —   —   1   0.5364   803_H_+1           803_E_+2   —   —   —   —   —   0.3214   803_E_+2           CNTL   0.6%   0.0%   27.6%   0.0%   24.4%   47.4%   CNTL           CASE   0.0%   5.6%   44.4%   0.0%   22.2%   33.3%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.2478                         0.5963   0.2248   0.1369   0.5509   0.1992   0.65   0.3174   0.5385   0.6246   0.0854   962_E_3       962_E_+2       0.3791   0.3768   0.2434   0.0858   0.229   0.3403   0.4079   0.1189   0.1552   0.3781   0.1263   962_E_+2       962_G_4           1   0.7616   0.4552   0.6851   0.6567   0.8356   0.529   0.5598   0.8179   0.4133   962_G_4       962_G_1               0.7656   0.3307   0.6798   0.8991   0.9987   0.6566   0.5303   0.9899   0.3312   962_G_1       962_G_2                   0.6172   0.3257   0.4824   0.557   0.1541   0.1814   0.6406   0.0754   962_G_2       962_G_6           —       —   0.4658   0.7235   0.6973   0.3602   0.5274   0.6737   0.3596   962_G_6       962_H_+2                   —   —   1   0.7252   0.287   0.8698   0.7496   0.4577   962_H_+2       962_M_+2   —       —       —   —   —   1   0.502   0.677   0.7965   0.755   962_M_+2       962_P_−2           —   —   —   —           0.2469   0.1296   0.4992   0.292   962_P_−2       962_Q_−1   —       —   —   —   —           —   0.4707   0.6638   0.2631   962_Q_−1       962_S_−1           —       —           —   —   —   0.6849   0.7862   962_S_−1       962_U_1               —   —                   —       0.2932   962_U_1       962_U_2           —   —   —                   —       —   962_U_2       962_V_−1           —   —   —   —   —           —   —   —   962_V_−1       962_V_+2           —       —   —               —   —   —   962_V_+2       962_Z_1               —   —               —   —   —       962_Z_1       CNTL   33.6%   13.0%   12.9%   30.8%   9.7%   177%   37.7%   13.2%   22.4%   21.7%   12.2%   1.9%   CNTL       CASE   50.0%    0.0%    7.1%   35.7%   0.0%    7.1%   35.7%   14.3%   40.0%   33.3%   14.3%   7.1%   CASE                                                     962_U_2   962_V_−1   962_V_+2   962_Z_1                                                         962_E_3   0.4772   0.6165   0.2995   0.1623   962_E_3           962_E_+2   0.1087   0.3523   0.0993   0.1578   962_E_+2           962_G_4   0.5146   0.874   0.4457   0.2758   962_G_4           962_G_1   0.4157   0.5854   0.6819   0.4627   962_G_1           962_G_2   0.1463   0.517   0.2801   0.2   962_G_2           962_G_6   0.4287   0.6038   0.4528   0.4868   962_G_6           962_H_+2   0.666   0.9967   0.7213   0.5899   962_H_+2           962_M_+2   0.588   0.9449   0.7439   0.5583   962_M_+2           962_P_−2   0.2324   0.3661   0.3176   0.2698   962_P_−2           962_Q_−1   0.3068   0.4758   0.4862   0.2157   962_Q_−1           962_S_−1   0.5596   0.946   0.6896   0.569   962_S_−1           962_U_1   0.2042   0.6576   0.2103   0.1691   962_U_1           962_U_2   0.315   0.4167   0.379   0.1139   962_U_2           962_V_−1       1   0.6162   0.5854   962_V_−1           962_V_+2           1   0.2332   962_V_+2           962_Z_1           —   0.3845   962_Z_1           CNTL   21.7%   35.4%   4.7%   35.5%   CNTL           CASE   35.7%   35.7%   0.0%   21.4%   CASE                        
     [0383] All SNP combinations in Tables 25, 26, and 27 that demonstrated a significant difference (p≦0.05) in the distribution of frequencies of the four haplotypes between the cases and the control populations were further analyzed to identify individual haplotypes that were also significant. Table 28 presents the haplotypes that were significantly associated, at the 0.05 level of significance, with the BHR phenotype. Haplotypes with higher allele frequency in the case population than in the control population acted as risk factors that increased the susceptibility to asthma. Haplotypes with lower allele frequencies in the case population than in the control population acted as protective factors that decreased the susceptibility to asthma. For Gene 845, three haplotypes were susceptibility haplotypes, associated with an increased risk of asthma at the 0.05 level of significance in the combined population. They were haplotypes G/G (SNPs R1/K−2, p=0.0144), C/T (SNPs K1/D−1, p=0.0035) and G/C (SNPs K−2/H+1, p=0.0153). One haplotype, C/C (SNPs K1/D−1, p=0.004), was protective in the combined population. In the UK population, seven haplotypes were susceptibility haplotypes. They were haplotypes T/G (SNPs R−1/J1, p=0.0209), G/T (SNPs K−2/D1 p=0.0378), G/C (SNPs J1/D1, p=0.0234), A/T (SNPs J1/D1, p=0.0003), C/T (SNPs H−1/D1, p=0.0389), C/T (SNPs D1/D-1, p=0.007) and T/T (SNPs D1/D−1, p=0.0326). There were two haplotypes that were protective in the UK population, A/C (SNPs J1/D1, p=0.0133) and C/C (SNPs D1/D−1, p=0.003). In the US population, haplotype C/G (SNPs K1/H+1, p=0.0494) was a protective haplotype. Two haplotypes were susceptibility haplotypes in the US population, T/C (SNPs P+1/H+1, p=0.0482) and C/C (SNPs K1/H+1, p=0.0329). For Gene 847, four haplotypes were protective in the US population. They were haplotypes G/C (SNPs K1/D−1, p=0.0393), G/G (SNPs K1/C+1, p=0.036), C/C (SNPs J+1/D−1, p=0.0386), C/G (SNPs J+1/C+1, p=0.0373). Seven haplotypes were susceptibility haplotypes in the US population. They were haplotypes G/C (SNPs K1/D−1, p=0.0164), G/A (SNPs K1/C+1, p=0.0217), C/T (SNPs J+1/E+1, p=0.0259), C/A (SNPs J+1/D−1, p=0.0165), C/A (SNPs J+1/C+1 0.0219), A/C (SNPs D−1/A2, p=0.0423) and A/C (SNPs C+1/A2, p=0.0495). For Gene 803, two haplotypes were protective in the US population. They were haplotypes G/C (SNPs K2/I1, p=0.047) and G/C (SNPs K2/E+2, p=0.047). For Gene 962, haplotype A/C (SNPs G2/S−1, p=0.0396) was a susceptibility haplotype in the UK population.  
                                   TABLE 28                           SNP                           COMBI-   HAPLO-   FREQUENCIES       P-       GENE   NATION   TYPE   CNTL   CASE   VALUE                                    BHR Combined       US and UK                                     845   R1/K−2   GG   0.56247   0.707124   0.0144       845   K1/D−1   CC   0.898545   0.797619   0.004       845   K1/D−1   CT   0.099078   0.202381   0.0035       845   K−2/H+1   GC   0.514469   0.665   0.0153                 BHR       UK Population                                     845   R−1/J1   TG   0   0.039657   0.0209       845   K−2/D1   GT   0   0.013974   0.0378       845   J1/D1   GC   0.365672   0.514095   0.0234       845   J1/D1   AC   0.634328   0.471596   0.0133       845   J1/D1   AT   0   0.014308   0.0003       845   H−1/D1   CT   0   0.013795   0.0389       845   D1/D−1   CC   0.907143   0.791667   0.003       845   D1/D−1   CT   0.092857   0.194444   0.007       845   D1/D−1   TT   0   0.013889   0.0326       962   G2/S−1   AC   0.010124   0.042804   0.0396                 BHR       US Population                                     845   P+1/H+1   TC   0.052119   0.214286   0.0482       845   K1/H+1   CC   0.798701   1   0.0329       845   K1/H+1   CG   0.201299   0   0.0494       847   K1/D−1   GA   0.750602   1   0.0164       847   K1/D−1   GC   0.176239   0   0.0393       847   K1/C+1   GA   0.745012   1   0.0217       847   K1/C+1   GG   0.181817   0   0.036       847   J+1/E+1   CT   0.791905   1   0.0259       847   J+1/D−1   CA   0.738791   1   0.0165       847   J+1/D−1   CC   0.176558   0   0.0386       847   J+1/C+1   CA   0.733303   1   0.0219       847   J+1/C+1   CG   0.182036   0   0.0373       847   D−1/A2   AC   0.772011   1   0.0423       847   C+1/A2   AC   0.761836   1   0.0495       803   K2/I1   GC   0.724359   0.5   0.047       803   K2/E+2   GC   0.724359   0.5   0.047                  
 
     [0384] c. Total IgE  
     [0385] In Tables 29, 30 and 31, the haplotype analysis (2-at-a-time) is presented for the combined, the UK and the US populations, respectively. A single SNP combination in Gene 845 is significant in the US population: SNPs R 1 &amp; R−1 (p=0.0355). Fourteen SNP combinations in Gene 962 are significant in the combined and in the UK and US population alone: SNPs E 3 &amp; G 1 (US p=0.0398), SNPs E+2 &amp; G 1 (combined p=0.0249), SNPs E+2 &amp; V−1 (combined p=0.0305), SNPs G 4 &amp; G 1 (combined p=0.0089, UK p=0.0282), SNPs G 4 &amp; G 6 (UK p=0.0376), SNPs G 4 &amp; Q−1 (US p=0.0263), SNPs G 4 &amp; U 2 (US p=0.0168), SNPs G 4 &amp; V+2 (US p=0.0052), SNPs G 1 &amp; P−2 (combined p=0.0268), SNPs G 1 &amp; Q−1 (combined p=0.0069, UK p=0.0375, US p=0.025), SNPs G 1 &amp; U 2 (US p=0.0194), SNPs G 6 &amp; S−1 (UK p=0.0112), SNPs H+2 &amp; S−1 (combined p=0.0426) and SNPs M+2 &amp; P−2 (US p=0.0096).  
               TABLE 29                       HAPLOTYPE ANALYSIS OF TOTAL IgE PHENOTYPE COMBINED US/UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.8877   0.1664   0.3567   0.9097   0.2478   0.5528   0.6568   0.9102   0.5597   0.7751   0.6319   0.699   0.921   0.7729   845_R_1       R_1       845 —     —   0.0901   0.1208   0.1986   0.0797   0.288   0.2058   0.2832   0.0682   0.2866   0.3337   0.322   0.1405   0.2124   845_R_−1       R_−1       845 —     —   —   0.1257   0.3338   0.1405   0.4922   0.321   0.3264   0.2647   0.4947   0.2845   0.318   0.275   0.3822   845_P_+1       P_+1        845 —     —   —   —   1   0.3383   0.424   0.6671   0.8301   0.5338   0.6229   0.7208   0.938   0.7972   0.6038   845_K_1       K_1       845 —     —   —   —   —   0.1677   0.2421   0.2833   0.2178   0.0993   0.3013   0.3282   0.2824   0.1951   0.2697   845_K_−2       K_−2       845 —     —   —   —   —   —   0.2952   0.0942   0.3088   0.4593   0.681   0.4093   0.6186   0.3818   0.4658   845_J_1       J_1       845 —     —   —   —   —   —   —   0.6062   0.815   0.2347   0.4244   0.6932   0.9265   0.7733   0.571   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   0.7609   0.5615   0.6564   0.3315   0.7179   0.8779   0.4486   845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   0.4431   0.4406   0.7   0.8354   0.3571   0.5568   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.4795   0.761   0.7321   0.6216   0.7728   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.6628   0.7036   0.8653   0.6024   845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —       1   0.9464   0.7782   845_F_+1       F_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   0.3966   0.8431   845_D_1       D_1       845 —     —   —   —       —   —   —   —   —   —   —   —   —   0.505   845_D_−1       D_−1       CNTL   14.8%   28.7%    6.5%   0.2%   28.9%   34.5%   37.1%   12.8%   19.6%   45.2%   13.2%   18.4%   0.2%    9.9%   CNTL       CASE   14.1%   21.1%   10.8%   0.0%   22.1%   40.0%   40.0%   11.5%   16.2%   41.4%   14.6%   18.5%   0.8%   12.1%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   1   0.7224   0.5704   0.9785   0.8175   0.4686   0.7671   847_K_1           847_J_+1   —   0.4732   0.4748   0.6465   0.4706   0.8183   0.5835   847_J_+1           847_E_+1   —   —   0.4629   0.5443   0.6655   0.8942   0.7853   847_E_+1           847_D_+1   —   —   —   0.7795   0.8749   0.9481   0.9318   847_D_−1           847_C_+1   —   —   —   —   0.3696   0.8263   0.7704   847_C_+1           847_A_2   —   —   —   —   —   0.7007   0.8952   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   4.9%   4.9%   12.6%   16.9%   17.9%   6.7%   1.0%   CNTL           CASE   5.0%   3.0%   15.2%   17.9%   21.5%   7.5%   0.8%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.1181   0.476   0.4027   0.361   874_R_+1           874_S_+1   —   0.8413   0.4528   0.4627   874_S_+1           874_T_−1   —   —   0.8447   0.4184   874_T_−1           874_V_−1   —   —   —   0.3785   874_V_−1           CNTL   39.9%   39.5%   48.6%   17.6%   CNTL           CASE   32.0%   40.4%   50.0%   21.0%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   0.3637   0.234   0.5258   0.517   0.5151   0.5526   803_K_3           803_K_2   —   0.1402   0.3257   0.3147   0.3245   0.3302   803_K_2           803_I_1   —   —   0.9113   0.9885   0.9273   0.6626   803_I_1           803_I_−1   —   —   —   1   0.7904   0.8594   803_I_−1           803_H_+1   —   —   —   —   0.7311   0.9108   803_H_+1           803_E_+2   —   —   —   —   —   0.8402   803_E_+2           CNTL   0.9%   0.2%   28.2%   0.2%   25.2%   44.2%   CNTL           CASE   2.2%   1.5%   28.8%   0.0%   23.5%   45.4%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.4753   0.1281   0.1867   0.1135   0.6053   0.556   0.3468   0.6678   0.8706   0.8684   0.5581   0.8916   962_E_3       962_E_+2   —   0.0677   0.0562                         0.1588   0.1748   0.074   0.1769   0.1882   0.2181   0.1578   0.1515   962_E_+2       962_G_4   —   —                                               0.1223   0.081   0.0657   0.1223   0.2134   0.232   0.0512   0.1698   962_G_4       962_G_1   —   —   —                         0.1715   0.0856                         0.1718                                               0.1315   0.1675   962_G_1       962_G_2   —   —   —   —   1   0.4859   0.5186   0.8108   0.9667   0.9888   0.4504   0.6718   962_G_2       962_G_6   —   —   —   —   —   0.3205   0.3003   0.2838   0.6461   0.6884   0.1011   0.168   962_G_6       962_H_+2   —   —   —   —   —   —   0.117   0.1524   0.4959   0.431                         0.5122   962_H_+2       962_M_+2   —   —   —   —   —   —   —   0.6553   0.7965   0.8171   0.7357   0.8275   962_M_+2       962_P_−2   —   —   —   —   —   —   —   —   0.7323   0.6335   0.6199   0.9552   962_P_−2       962_Q_−1   —   —   —   —   —   —   —   —   —   0.8195   0.6502   0.9595   962_Q_−1       962_S_−1   —   —   —   —   —   —   —   —   —   —   0.3507   0.5865   962_S_−1       962_U_1   —   —   —   —   —   —   —   —   —   —   —   0.7821   962_U_1       962_U_2   —   —   —   —   —   —   —   —   —   —   —   —   962_U_2       962_V_−1   —   —   —   —   —   —   —   —   —   —   —   —   962_V_−1       962_V_+2   —   —   —   —   —   —   —   —   —   —   —   —   962_V_+2       962_Z_1   —   —   —   —   —   —   —   —   —   —   —   —   962_Z_1       CNTL   35.6%   12.7%   13.6%   27.2%   7.6%   20.4%   41.5%   12.7%   23.8%   23.7%   11.4%   3.0%   CNTL       CASE   32.1%    6.8%    7.1%   37.0%   7.7%   16.2%   34.0%   10.7%   25.4%   24.6%    8.3%   3.6%   CASE                                                     962_U_2   962_V_−1   962_V_+2   962_Z_1                                                         962_E_3   0.8737   0.2619   0.4308   0.45   962_E_3           962_E_+2   0.2713                         0.1741   0.184   962_E_+2           962_G_4   0.2206   0.1478   0.2075   0.2068   962_G_4           962_G_1                         0.1068   0.1444   0.1705   962_G_1           962_G_2   0.9814   0.805   0.9191   0.9782   962_G_2           962_G_6   0.7122   0.5476   0.5849   0.6686   962_G_6           962_H_+2   0.2878   0.1857   0.2384   0.2674   962_H_+2           962_M_+2   0.4814   0.6648   0.6777   0.9384   962_M_+2           962_P_−2   0.9691   0.8527   0.7035   0.6705   962_P_−2           962_Q_−1   0.7251   0.7745   0.8439   0.832   962_Q_−1           962_S_−1   0.7682   0.473   0.4304   0.784   962_S_−1           962_U_1   0.9682   0.4878   0.8   0.8671   962_U_1           962_U_2   1   0.6732   0.8443   0.9975   962_U_2           962_V_−1   —   0.3994   0.8052   0.6563   962_V_−1           962_V_+2   —   —   0.8112   0.848   962_V_+2           962_Z_1   —   —   —   1   962_Z_1           CNTL   23.8%   34.8%   4.5%   31.9%   CNTL           CASE   23.9%   30.4%   3.5%   31.5%   CASE                      
 
     [0386]               TABLE 30                       HAPLOTYPE ANALYSIS OF TOTAL IgE PHENOTYPE UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.6245   0.4023   0.5577   0.7546   0.4747   0.6289   0.864   0.8681   0.4819   0.6939   0.5258   0.5721   0.3188   0.6705   845_R_1       R_1       845 —     —   0.2308   0.3701   0.4518   0.5377   0.3954   0.4301   0.3487   0.2214   0.4435   0.3928   0.3966   0.0989   0.4124   845_R_−1       R_−1       845 —     —   —   0.3784   0.5805   0.382   0.8256   0.4869   0.6381   0.5489   0.7792   0.5012   0.6447   0.2661   0.4538   845_P_+1       P_+1       845 —     —   —   —   1   0.4822   0.6095   0.726   0.9105   0.6231   0.6843   0.5994   0.9638   0.2114   0.5816   845_K_1       K_1       845 —     —   —   —   —   0.2842   0.4374   0.4736   0.3916   0.262   0.4658   0.4576   0.4679   0.1238   0.4401   845_K_−2       K_−2       845 —     —   —   —   —   —   0.4798   0.264   0.559   0.6743   0.8718   0.561   0.8951   0.2368   0.7503   845_J_1       J_1       845 —     —   —   —   —   —   —   0.6392   0.8437   0.3453   0.5816   0.6365   0.9516   0.2641   0.5881   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   0.8603   0.6469   0.6953   0.2242   0.7965   0.2795   0.7392   845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   0.5564   0.5493   0.68   0.9185   0.1306   0.6331   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.4918   0.7011   0.7365   0.2415   0.7078   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.5116   0.3714   0.218   0.5832   845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   1   0.3304   0.7673   845_F_+1       F_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   0.267   0.2239   845_D_1       D_1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   —   0.4474   845_D_−1       D_−1       CNTL   13.6%   26.6%   6.4%   0.4%   27.0%   36.6%   37.5%   12.6%   19.3%   43.6%   13.2%   18.8%   0.0%   9.3%   CNTL       CASE   15.4%   20.2%   9.4%   0.0%   21.0%   40.6%   40.6%   11.3%   16.0%   39.6%   16.0%   18.9%   1.0%   11.8%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   1   0.9807   0.3563   0.7223   0.4804   0.2596   0.9246   847_K_1           847_J_+1   —   1   0.4687   0.5717   0.3727   0.7772   0.8857   847_J_+1           847_E_+1   —   —   0.2494   0.2263   0.3632   0.5525   0.6005   847_E_+1           847_D_−1   —   —   —   0.3355   0.2587   0.708   0.7655   847_D_−1           847_C_+1   —   —   —   —   0.1502   0.5014   0.5763   847_C_+1           847_A_2   —   —   —   —   —   0.474   0.7139   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   3.6%   2.9%   12.8%   16.5%   17.8%   5.4%   1.3%   CNTL           CASE   3.2%   2.8%   17.9%   21.6%   24.5%   7.4%   0.9%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.1597   0.4766   0.3645   0.4563   874_R_+1           874_S_+1   —   0.8191   0.3188   0.6485   874_S_+1           874_T_−1   —   —   0.5794   0.5573   874_T_−1           874_V_−1   —   —   —   0.4743   874_V_−1           CNTL   41.5%   38.0%   48.9%   16.9%   CNTL           CASE   33.3%   39.5%   52.6%   19.8%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   0.3645   0.2827   0.3971   0.5477   0.5264   0.4218   803_K_3           803_K_2   —   0.2083   0.5861   0.6613   0.6176   0.2997   803_K_2           803_I_1   —   —   0.7033   0.753   0.6955   0.5913   803_I_1           803_I_−1   —   —   —   1   0.7974   0.4821   803_I_−1           803_H_+1   —   —   —   —   0.7028   0.5103   803_H_+1           803_E_+2   —   —   —   —   —   0.3091   803_E_+2           CNTL   1.1%   0.4%   28.6%   0.4%   25.7%   42.4%   CNTL           CASE   2.6%   1.7%   26.3%   0.0%   23.7%   48.2%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.2974   02915   0.204   0.087   0.6881   0.2484   0.311   0.5433   0.6727   0.6634   0.4786   0.6045   962_E_3       962_E_+2   —   0.1645   0.1231   0.1181   0.158   0.082   0.2014   0.2432   0.2642   0.2958   0.2729   0.2645   692_E_+2       962_G_4   —   —   0.0904                         0.1929                         0.1096   0.2014   0.2795   0.2753   0.1095   0.2195   962_G_4       962_G_1   —   —   —   0.0695   0.3054   0.1099   0.1424   0.1657   0.0649                         0.1516   0.1315   962_G_1       962_G_2   —   —       —   0.666   0.2817   0.5762   0.5679   0.8178   0.774   0.3131   0.6239   962_G_2       962_G_6   —           —   —   0.1218   0.172   0.0727   0.0853   0.0695                         0.1155   962_G_6       962_H_+2   —   —       —   —   —   0.1834   0.3028   0.4322   0.3945   0.1222   0.4941   962_H_+2       962_M_+2   —   —       —   —   —   —   0.3811   0.3722   0.3156   0.6192   0.5613   962_M_+2       962_P_−2   —   —       —   —   —   —   —   0.5173   0.33   0.3482   0.922   962_P_−2       962_Q_−1   —   —       —   —   —   —   —   —   0.4355   0.3319   0.8763   962_Q_−1       962_S_−1   —   —           —       —   —           0.2008   0.4341   962_S_−1       962_U_1   —           —   —   —   —   —       —   —   1   962_U_1       962_U_2   —               —   —   —       —   —   —   —   962_U_2       962_V_−1   —           —   —   —   —       —   —   —   —   962_V_−1       962_V_+2   —           —   —   —   —       —   —       —   962_V_+2       962_Z_1   —           —   —   —   —       —   —       —   962_Z_1       CNTL   36.8%   12.5%140%   14.0%   25.2%   6.4%   21.7%   43.6%   12.4%   24.6%   24.8%   10.9%   3.7%   CNTL       CASE   31.0%    7.4%    7.8%   34.4%   7.6%   14.4%   35.8%    8.6%   21.2%   20.7%    6.7%   3.4%   CASE                                                     962_U_2   962_V_−1   962_V_+2   962_Z_1                                                         962_E_3   0.5419   0.3712   0.5548   0.3789   962_E_3           962_E_+2   0.2659   0.0886   0.3613   0.3826   692_E_+2           962_G_4   0.2152   0.3258   0.2153   0.3197   962_G_4           962_G_1   0.1043   0.1972   0.3573   0.2492   962_G_1           962_G_2   0.6705   0.6619   0.5615   0.7564   962_G_2           962_G_6   0.3091   0.1323   0.2743   0.3044   962_G_6           962_H_+2   0.2633   0.4808   0.2801   0.4622   962_H_+2           962_M_+2   0.1131   0.6542   0.3507   0.5703   962_M_+2           962_P_−2   0.948   0.6796   0.7363   0.7975   962_P_−2           962_Q_−1   0.7428   0.6208   0.8437   0.7718   962_Q_−1           962_S_−1   0.3126   0.5109   0.2025   0.3561   962_S_−1           962_U_1   0.6355   0.3439   0.8724   0.7934   962_U_1           962_U_2   0.297   0.3151   0.7156   0.6601   962_U_2           962_V_−1   —   0.5516   0.7585   0.8999   962_V_−1           962_V_+2       —   0.7845   0.7238   962_V_+2           962_Z_1       —       0.4837   962_Z_1           CNTL   25.0%   34.4%   4.5%   30.0%   CNTL           CASE   19.5%   31.0%   3.3%   33.6%   CASE                        
     [0387]               TABLE 31                       HAPLOTYPE ANALYSIS OF TOTAL IgE PHENOTYPE US POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D —1     845_D_+1                                                                                     845 —     0.3763                         0.4291   0.2741   0.061   0.5114   0.3395   0.6041   0.5582   0.6003   0.5553   0.6409   0.341   0.5721   845_R_1       R_1       845 —     —   0.6371   0.3579   0.4625   0.7658   0.7312   0.7173   0.8947   0.5329   0.7777   0.789   0.788   0.5082   0.698   845_R_−1       R_−1       845 —     —   —   0.1002   0.2853   0.3643   0.3915   0.3745   0.3972   0.4378   0.4423   0.3215   0.4794   0.3904   0.5397   845_P_+1       P_+1       845 —     —   —   —   1   0.6082   0.6006   0.8939   0.8958   0.6015   0.9926   0.454   0.8896   0.8236   0.7791   845_K_1       K_1       845 —     —   —   —   —   0.8075   0.7627   0.8266   0.8464   0.3925   0.8264   0.7076   0.8454   0.6625   0.8512   845_K_−2       K_−2       845 —     —   —   —   —   —   0.6376   0.689   0.7509   0.8291   0.7813   0.5999   0.8772   0.6346   0.7247   845_J_1       J_1       845 —     —   —   —   —   —   —   1   0.9932   0.8628   0.8851   0.7794   0.9827   0.9724   0.9371   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   1   0.8924   0.9739   0.533   0.9293   0.9712   0.7797   845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   1   0.8797   0.7679   0.9337   0.6599   0.908   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   1   0.837   0.9597   0.9746   0.9407   845_H_−1       H_−1       845 —         —   —   —   —   —       —   —   —   0.7426   0.6413   0.6061   0.4484   845_G_+1       G_+1       845 —         —   —   —   —   —       —   —   —   —   1   0.9585   0.9481   845_F_+1       F_+1       845 —         —   —   —   —   —   —   —   —   —   —   —   1   0.725   845_D_1       D_1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   —   0.7202   845_D_−1       D_−1       CNTL   17.1%   32.5%    6.5%   0.0%   32.5%   30.9%   36.4%   13.3%   20.1%   48.1%   13.2%   17.5%   0.7%   11.0%   CNTL       CASE    8.3%   25.0%   16.7%   0.0%   27.3%   37.5%   37.5%   12.5%   16.7%   50.0%    8.3%   16.7%   0.0%   13.6%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   0.4387   0.6112   0.3997   0.2007   0.3158   0.8474   0.7237   847_K_1           847_J_+1   —   0.6961   0.2419   0.1401   0.3176   0.207   0.5424   847_J_+1           847_E_+1   —   —   0.3158   0.1564   0.4302   0.5092   0.2996   847_E_+1           847_D_−1   —   —   —   0.1308   0.1493   0.2724   0.1859   847_D_−1           847_C_+1   —   —   —   —   0.378   0.5464   0.3744   847_C_+1           847_A_2   —   —   —   —   —   1   0.9789   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL    7.3%   8.4%   12.3%   17.6%   18.2%   9.1%   0.7%   CNTL           CASE   11.5%   3.8%    3.8%    4.2%    8.3%   7.7%   0.0%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.3317   0.4639   0.5461   0.533   874_R_+1           874_S_+1   —   0.8201   0.3993   0.6175   874_S_+1           874_T_−1   —   —   0.3647   0.5908   874_T_−1           874_V_−1   —   —   —   0.3924   874_V_−1           CNTL   37.0%   42.2%   48.1%   18.8%   CNTL           CASE   25.0%   45.5%   36.4%   27.3%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   1   0.7837   0.222   0.7897   0.8098   0.2268   803_K_3           803_K_2   —   1   0.1237   1   0.9255   0.117   803_K_2           803_I_1   —   —   0.1714   0.1213   0.3365   0.2921   803_I_1           803_I_−1   —   —   —   1   0.9248   0.11   803_I_−1           803_H_+1   —   —   —   —   1   0.2773   803_H_+1           803_E_+2   —   —   —   —   —   0.1375   803_E_+2           CNTL   0.6%   0.0%   27.6%   0.0%   24.4%   47.4%   CNTL           CASE   0.0%   0.0%   44.4%   0.0%   22.2%   27.8%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_D_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.8172   0.2115   0.2866                         0.5867   0.8474   0.1143   0.5722                         0.0848   0.6602   0.2048   692_E_3       962_E_+2   —   0.316   0.4477   0.1729   0.5175   0.2022   0.2203   0.3776                                               0.4254   0.3649   962_E_+2       962_G_4       —   0.3133   0.0863   0.1481   0.3626   0.32   0.3242                                               0.4093   0.2215   962_G_4       962_G_1   —   —       0.1014   0.3663   0.2943   0.1246   0.2333                                               0.2458   0.0679   962_G_1       962_G_2       —       —   1   0.9185   0.5113   0.8406                         0.0728   0.9624   0.8903   962_G_2       962_G_6               —   —   0.4013   0.6844   0.659   0.0884   0.0934   0.699   0.5045   962_Q_6       962_H_+2       —       —   —   —   0.2614   0.2184   0.0694   0.101   0.3392   0.3355   962_H_+2       962_M_+2           —           —   —   0.3451                                               0.4484   0.5179   962_M_+2       962_P_−2               —       —   —   —                                                                                           962_P_−2       962_Q_−1                               —                             0.0676   0.0603   962_Q_−1       962_S_−1           —           —   —   —   —   0.5172   0.8519   962_S_−1       962_U_1       —   —       —   —   —       —   —   0.4129   962_U_1       962_U_2       —   —           —   —       —   —   —   962_U_2       962_V_−1                   —   —   —       —   —   —   962_V_−1       962_V_+2           —               —       —   —   —   962_V_+2       962_Z_1           —           —           —   —   —   962_Z_1       CNTL   33.6%   13.0%   12.9%   30.8%   9.7%   17.7%   37.7%   13.2%   22.4%   21.7%   12.2%   1.9%   CNTL       CASE   37.5%    4.2%    4.2%   50.0%   8.3%   25.0%   25.0%   20.8%   50.0%   45.5%   16.7%   4.5%   CASE                                                     962_U_2   962_V_−1   962_V_+2   962_Z_1                                                         962_E_3   0.0641   0.5184   0.807   0.2894   692_E_3           962_E_+2                         0.383   0.5794   0.1121   962_E_+2           962_G_4                         0.4162                         0.2008   962_G_4           962_G_1                         0.0625   0.1196   0.1409   962_G_1           962_G_2                         0.6958   0.4654   0.3824   962_G_2           962_G_6   0.093   0.0671   0.7585   0.4835   962_Q_6           962_H_+2   0.0822   0.074   0.5836   0.2512   962_H_+2           962_M_+2                         0.6632   0.7877   0.5007   962_M_+2           962_P_−2                         0.01951                         0.0672   962_P_−2           962_Q_−1                                                                     0.1148   962_Q_−1           962_S_−1                         0.7916   0.8609   0.4923   962_S_−1           962_U_1                         0.8537   0.8558   0.184   962_U_1           962_U_2                                                                     0.0705   962_U_2           962_V_−1   —   0.6278   0.1653   0.0863   962_V_−1           962_V_+2   —       1   0.4925   962_V_+2           962_Z_1               0.2483   962_Z_1           CNTL   21.7%   35.4%   4.7%   35.5%   CNTL           CASE   45.8%   27.3%   4.2%   20.8%   CASE                        
     [0388] All SNP combinations in Tables 29, 30, and 31 that demonstrated a significant difference (p≦0.05) in the distribution of frequencies of the four haplotypes between the cases and the control populations were further analyzed to identify individual haplotypes that were also significant. Table 32 presents the haplotypes that were significantly associated, at the 0.05 level of significance, with the IgE phenotype. Haplotypes with higher allele frequency in the case population than in the control population acted as risk factors that increased the susceptibility to asthma. Haplotypes with lower allele frequencies in the case population than in the control population acted as protective factors that decreased the susceptibility to asthma. For Gene 845, a single susceptibility haplotype G/C (SNPs R1/R−1, p=0.0287) was significant in the US population. For Gene 962, four haplotypes were susceptibility haplotypes in the combined population. They were haplotypes T/A (SNPs E+2/G1, p=0.0163), G/A (SNPs G4/G1, p=0.0096), A/A (SNPs G1/P−2, p=0.0121) and A/A (SNPs G1/Q-1, p=0.0018). Two haplotypes were protective in the combined population. They were C/T (SNPs E+2/V−-1, p=0.0386) and G/A (SNPs G1/Q−1, p=0.0196). Four haplotypes were susceptibility haplotypes in the UK population. They were haplotypes G/A (SNPs G4/G1, p=0.0104), G/C (SNPs G4/G6, p=0.0156), A/A (SNPs G1/Q−1, p=0.041) and C/G (SNPs G6/S−1, p=0.0057). Three haplotypes were protective in the UK population. They were haplotypes G/A (SNPs G1/Q−1, p=0.0138), C/C (SNPs G6/S−1, p=0.0401) and T/G (SNPs G6/S−1, p=0.0255). Six haplotypes were susceptibility haplotypes in the US population. They were G/A (SNPs G4/Q−1, p=0.0096), G/T (SNPs G4/U2, p=0.0086), A/A (SNPs G4N+2, p=0.0305), A/A (SNPs G1/Q−1, p=0.0072), A/T (SNPs G1/U2, p=0.0062) and G/A (SNPs M+2/P−2, p=0.0009). The haplotypes T/G (SNPs E3/G1, p=0.0367) and G/G (SNPs M+2/P−2, p=0.0001) were protective haplotypes in the US population.  
                                   TABLE 32                           SNP                           COMBI-   HAPLO-   FREQUENCIES       P-       GENE   NATION   TYPE   CNTL   CASE   VALUE                                    Total IgE Combined       US and UK                                     962   E+2/G1   TA   0.237558   0.340794   0.0163       962   E+2/V−1   CT   0.049664   0   0.0386       962   G4/G1   GA   0.208523   0.317136   0.0096       962   G1/P−2   AA   0.057605   0.140911   0.0121       962   G1/Q−1   AA   0.049187   0.148707   0.0018       962   G1/Q−1   GA   0.187956   0.094082   0.0196                 Total IgE       UK Population                                     962   G4/G1   GA   0.175073   0.289291   0.0104       962   G4/G6   GC   0.640687   0.77847   0.0156       962   G1/Q−1   AA   0.050665   0.116778   0.041       962   G1/Q−1   GA   0.197425   0.088239   0.0138       962   G6/S−1   CC   0.101659   0.031721   0.0401       962   G6/S−1   CG   0.681786   0.821243   0.0057       962   G6/S−1   TG   0.208433   0.11209   0.0255                 Total IgE       US Population                                     845   R1/R−1   GC   0.504855   0.75   0.0287       962   E3/G1   TG   0.383347   0.125   0.0367       962   G4/Q−1   GA   0.192645   0.410714   0.0096       962   G4/U2   GT   0.191643   0.416667   0.0086       962   G4/V+2   AA   0   0.041667   0.0305       962   G1/Q−1   AA   0.042798   0.29779   0.0072       962   G1/U2   AT   0.039558   0.286625   0.0068       962   M+2/P−2   GG   0.643053   0.263889   0.0001       962   M+2/P−2   GA   0.224358   0.527778   0.0009                  
 
     [0389] d. Specific IgE  
     [0390] In Tables 33, 34 and 35, the haplotype analysis (2-at-a-time) is presented for the combined, the UK and the US populations, respectively. Two SNP combinations in Gene 845 are significant in the US population: SNPs R 1 &amp; R−1 (p=0.0227) and SNPs R 1 &amp; K−2 (p=0.0293). A single SNP combination in Gene 847 is significant in the US population: SNPs J+1 &amp; D−1 (p=0.0341). Three SNP combinations in Gene 803 are significant in the US population: SNPs K 2 &amp; I 1 (p=0.0469), SNPs K 2 &amp; I−1 (p=0.0322) and SNPs K 2 &amp; E+2 (p=0.0212). Sixteen SNP combinations in Gene 962 are significant in the combined and in the UK and US population alone: SNPs E 3 &amp; G 1 (US p=0.0281), SNPs G 4 &amp; G 1 (combined p=0.0047, UK p=0.0351), SNPs G 4 &amp; S−1 (combined p=0.0064), SNPs G 4 &amp; U 2 (US p=0.0386), SNPs G 4 &amp; V+2 (US p=0.0366), SNPs G 1 &amp; M+2 (combined p=0.0184, UK p=0.0049), SNPs G 1 &amp; P−2 (combined p=0.0235), SNPs G 1 &amp; Q−1 (combined p=0.0144, US p=0.0265), SNPs G 1 &amp; S−1 (combined p=0.0051, UK p=0.00055), SNPs G 1 &amp; U 2 (combined p=0.0213, US p=0.0256), SNPs G 6 &amp; S−1 (UK p=0.00021), SNPs G 6 &amp; V−1 (UK p=0.0143), SNPs Q−1 &amp; V−1 (US p=0.023), SNPs U1 &amp; Z1 (US p=0.0328), SNPs U 2 &amp; V−1 (US p=0.0239) and SNPs U 2 &amp; V+2 (US p=0.0387).  
               TABLE 33                       HAPLOTYPE ANALYSIS OF SPECIFIC IgE PHENOTYPE COMBINED US/UK POPULATION                                                                                                845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1   845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                                     845 —     0.2296   0.1518                         0.3714   0.1807   0.1629   0.3673   0.3834   0.1673   0.2708   0.3605   0.3813   0.1999   0.1281   845_R_1       R_1       845 —     —   0.3572                         0.4822   0.3161   0.2909   0.1797   0.6834   0.0798   0.7266   0.7126   0.7033   0.3785   0.1726   845_R_−1       R_31 1       845 —     —   —                                                                     0.0745   0.0779   0.054                         0.0731                                                                     0.0768   845_P_+1       P_+1       845 —     —   —   —   1   0.5052   0.1554   0.4826   0.791   0.2566   0.5345   0.7481   0.7973   0.7413   0.1938   845_K_1       K_1       845 —         —   —   —   0.4121   0.1831   0.226   0.5452   0.0913   0.6269   0.6766   0.6511   0.4105   0.17   845_K_−2       K_−2       845 —     —   —   —   —   —   0.0856   0.1835   0.0905   0.1172   0.329   0.0883   0.1606   0.1449   0.106   845_J_1       J_1       845 —     —   —   —   —   —   —   0.391   0.5301   0.2668   0.3866   0.5501   0.7273   0.3249   0.1999   845_J_−1       J_−1       845 —     —   —   —   —   —   —   —   0.8746   0.2215   0.6014   0.5279   0.7317   0.8892   0.211   845_I_−1       I_−1       845 —     —   —   —   —   —   —   —   —   0.1414   0.1415   0.3128   0.3392   0.1094   0.0821   845_H_+1       H_+1       845 —     —   —   —   —   —   —   —   —   —   0.4045   0.7055   0.7036   0.4819   0.3251   845_H_−1       H_−1       845 —     —   —   —   —   —   —   —   —   —   —   0.7635   0.9483   0.8866   0.2038   845_G_+1       G_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   0.8944   0.9094   0.2005   845_F_+1       F_+1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   0.3743   0.1541   845_D_1       D_1       845 —     —   —   —   —   —   —   —   —   —   —   —   —   —   0.0931   845_D_−1       D_−1       CNTL   14.8%   28.7%    6.5%   0.2%   28.9%   34.5%   37.1%   12.8%   19.6%   45.2%   13.2%   18.4%   0.2%    9.9%   CNTL       CASE   10.2%   24.2%   14.2%   0.0%   24.6%   43.3%   32.5%   11.7%   13.3%   40.7%   14.2%   19.2%   0.9%   15.8%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                     847_K_1   1   0.2108   0.5992   0.9672   0.8047   0.4804   0.7265   847_K_1           847_J_+1   —   0.1282   0.1488   0.2185   0.1525   0.188   0.198   847_J_+1           847_E_+1       —   0.4567   0.5769   0.6622   0.8442   0.7965   847_E_+1           847_D_−1       —       0.8861   0.8465   0.9751   0.943   847_D_−1           847_C_+1   —   —   —   —   0.4345   0.801   0.7925   847_C_+1           847_A_2   —   —   —   —   —   0.6925   0.833   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   4.9%   4.9%   12.6%   16.9%   17.9%   6.7%   1.0%   CNTL           CASE   4.3%   1.6%   15.1%   17.6%   21.4%   7.8%   0.8%   CASE                                                         874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                         874_R_+1   0.1645   0.52   0.4011   0.5423   874_R_+1           874_S_+1       0.7578   0.4091   0.7481   874_S_+1           874_T_−1   —   —   0.9204   0.8202   874_T_−1           874_V_−1       —   —   0.7951   874_V_−1           CNTL   39.9%   39.5%   48.6%   17.6%   CNTL           CASE   32.5%   41.4%   49.2%   18.5%   CASE                                                                 803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                 803_K_3   1   0.4344   0.9062   0.9978   0.969   0.9789   803_K_3           803_K_2   —   0.1402   0.3256   0.3166   0.3845   0.3316   803_K_2           803_I_1   —   —   0.9108   0.8981   0.9528   0.8027   803_I_1           803_I_−1   —   —   —   1   0.9445   0.9941   803_I_−1           803_H_+1   —   —   —   —   0.9094   0.8957   803_H_+1           803_E_+2   —   —       —   —   1   803_E_+2           CNTL   0.9%   0.2%   28.2%   0.2%   25.2%   44.2%   CNTL           CASE   0.7%   1.5%   27.3%   0.0%   25.8%   44.6%   CASE                                                                                 962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2   962_P_−2   962_Q_−1   962_S_−1   962_U_1                                                                             962_E_3   0.6744   0.4225   0.3457   0.1286   0.4144   0.7862   0.3675   0.112   0.7783   0.7556                         0.8311   962_E_3       962_E_+2   —   0.2273   0.1035   0.0705   0.6363   0.5865   0.3159   0.0889   0.2515   0.2958                         0.4087   962_E_+2       962_G_4   —   —   0.0891                         0.2229   0.2633   0.2078                         0.2325   0.2413                         0.1943   962_G_4       962_G_1   —   —   —                         0.1604   0.0767   0.0529                                                                                           0.0854   962_G_1       962_G_2   —   —   —   —   0.8546   0.9507   0.5882   0.1948   0.7999   0.8257                         0.1274   962_G_2       962_G_6   —   —   —   —   —   0.6158   0.5057   0.1446   0.6043   0.6193                         0.1287   962_G_6       962_H_+2   —   —   —   —   —   —   0.2288   0.0722   0.4866   0.4064                         0.5704   962_H_+2       962_M_+2   —   —   —   —   —   —   —                         0.0925   0.1035                         0.0938   962_M_+2       962_P_−2   —   —   —   —   —   —   —   —   0.3568   0.8098                         0.6846   962_P_−2       962_Q_−1   —   —   —   —   —   —   —   —   —   0.3505                         0.6508   962_Q_−1       962_S_−1   —   —   —   —   —   —   —   —   —   —                                               962_S_−1       962_U_1   —   —   —   —   —   —   —   —   —   —   —   0.4086   962_U_1       962_U_2   —   —           —   —   —   —   —   —   —   —   962_U_2       962_V_−1   —   —   —       —   —   —   —   —   —   —   —   962_V_−1       962_V_+2   —   —   —   —   —   —   —   —   —   —   —   —   962_V_+2       962_Z_1   —   —   —   —   —   —   —   —   —   —   —   —   962_Z_1       CNTL   35.6%   12.7%   13.6%   27.2%   7.6%   20.4%   41.5%   12.7%   23.8%   23.7%   11.4%   3.0%   CNTL       CASE   33.1%    8.7%    7.7%   37.7%   8.1%   18.2%   35.3%    6.2%   28.0%   28.1%    3.7%   4.6%   CASE                                                     962_U_2   962_V_−1   962_V_+2   962_Z_1                                                         962_E_3   0.9381   0.2573   0.7005   0.7193   962_E_3           962_E_+2   0.419   0.3405   0.4616   0.4665   962_E_+2           962_G_4   0.3096   0.262   0.335   0.1846   962_G_4           962_G_1                         0.0946   0.1697   0.1218   962_G_1           962_G_2   0.9647   0.8981   0.9379   0.8667   962_G_2           962_G_6   0.9029   0.539   0.523   0.7072   962_G_6           962_H_+2   0.3779   0.1938   0.3487   0.4438   962_H_+2           962_M_+2   0.112   0.1275   0.0974   0.1731   962_M_+2           962_P_−2   0.3626   0.8466   0.6076   0.4826   962_P_−2           962_Q_−1   0.6619   0.6842   0.7026   0.553   962_Q_−1           962_S_−1                                                                     962 —                             S_−1           962_U_1   0.8632   0.5495   0.6703   0.343   962_U_1           962_U_2   0.7291   0.7724   0.8708   0.7266   962_U_2           962_V_−1   —   0.456   0.8624   0.6423   962_V_−1           962_V_+2   —   —   0.8108   0.6306   962_V_+2           962_Z_1   —       —   0.4601   962_Z_1           CNTL   23.8%   34.8%   4.5%   31.9%   CNTL           CASE   25.4%   31.1%   3.7%   28.3%   CASE                      
 
     [0391]               TABLE 34                       HAPLOTYPE ANALYSIS OF SPECIFIC IgE PHENOTYPE UK POPULATION                                                                        845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1                                                                         845_R_1   0.7179   0.6166   0.2644   0.7802   0.6552   0.5648   0.7964   845_R_1           845_R_−1   —   0.4875   0.2588   0.6508   0.6762   0.5075   0.4611   845_R_−1           845_P_+1           0.0724   0.2294   0.27   0.3931   0.2586   845_P_+1           845_K_1       —   —   1   0.6585   0.4304   0.6677   845_K_1           845_K_−2               —   0.5747   0.4925   0.5387   845_K_−2           845_J_1                   —   0.3119   0.5036   845_J_1           845_J_−1           —   —   —   —   0.6131   845_J_−1           845_I_−1   —   —   —   —   —   —   —   845_I_−1           845_H_+1       —   —   —   —   —   —   845_H_+1           845_H_−1       —   —   —   —   —   —   845_H_−1           845_G_+1   —   —   —   —   —   —   —   845_G_+1           845_F_+1   —   —   —   —   —   —   —   845_F_+1           845_D_1   —       —   —   —   —   —   845_D_1           845_D_−1   —       —   —   —   —   —   845_D_−1           CNTL   13.6%   26.6%   6.4%   0.4%   27.0%   36.6%   37.5%   CNTL           CASE   11.6%   22.7%   12.5%   0.0%   23.3%   43.2%   34.1%   CASE                                                                 845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                         845_R_1   0.8368   0.3811   0.6567   0.5634   0.5657   0.1807   0.3181   845_R_1           845_R_−1   0.675   0.2615   0.7534   0.6647   0.7616   0.1752   0.3296   845_R_−1           845_P_+1   0.2596   0.1602   0.348   0.2028   0.2206   0.0811   0.2774   845_P_+1           845_K_1   0.8109   0.425   0.5828   0.5418   0.7533   0.1398   0.3064   845_K_1           845_K_−2   0.7254   0.2937   0.7282   0.7126   0.7917   0.1835   0.3029   845_K_−2           845_J_1   0.3359   0.3591   0.7922   0.3446   0.5693   0.132   0.3158   845_J_1           845_J_−1   0.7402   0.4496   0.6547   0.5778   0.9237   0.1777   0.3385   845_J_−1           845_I_−1   0.852   0.3828   0.6398   0.2937   0.7773   0.2669   0.3774   845_I_−1           845_H_+1   —   0.2667   0.2899   0.4678   0.5499   0.0519   0.192   845_H_+1           845_H_−1   —   —   0.459   0.6689   0.7392   0.1676   0.1996   845_H_−1           845_G_+1   —   —   —   0.5956   0.7324   0.1832   0.2585   845_G_+1           845_F_+1   —   —   —   —   0.757   0.2616   0.2757   845_F_+1           845_D_1   —   —   —   —   —   0.235   0.0739   845_D_1           845_D_−1   —   —   —   —   —   —   0.1601   845_D_−1           CNTL   12.6%   19.3%   43.6%   13.2%   18.8%   0.0%   9.3%   CNTL           CASE   11.4%   13.6%   38.6%   15.9%   20.5%   1.2%   15.1%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                         847_K_1   1   0.556   0.33   0.5504   0.3852   0.446   0.9021   847_K_1           847_J_+1   —   0.461   0.2494   0.28   0.1971   0.6781   0.6582   847_J_+1           847_E_+1   —   —   0.1653   0.1659   0.2652   0.4232   0.4364   847_E_+1           847_D_−1       —   —   0.1853   0.1276   0.5154   0.7086   847_D_−1           847_C_+1   —   —   —   —   0.0964   0.272   0.33   847_C_+1           847_A_2   —   —   —   —   —   0.6132   0.8312   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   3.6%   2.9%   12.8%   16.5%   17.8%   5.4%   1.3%   CNTL           CASE   2.5%   1.1%   18.9%   23.1%   26.1%   6.5%   1.1%   CASE                                                     874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                             874_R_+1   0.1412   0.332   0.2742   0.4802   874_R_+1           874_S_+1   —   0.7215   0.4266   0.8159   874_S_+1           874_T_−1       —   0.7309   0.8326   874_T_−1           874_V_−1   —   —   —   0.7623   874_V_−1           CNTL   41.5%   38.0%   48.9%   16.9%   CNTL           CASE   32.3%   40.2%   51.0%   18.3%   CASE                                                             803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                     803_K_3   1   0.9362   0.6485   0.9952   0.9915   0.8117   803_K_3           803_K_2   —   0.4764   0.7517   0.993   0.5925   0.7175   803_K_2           803_I_1   —   —   0.4281   0.5416   0.5808   0.5877   803_I_1           803_I_−1   —   —   —   1   0.9705   0.4939   803_I_−1           803_H_+1   —   —   —   —   1   0.4115   803_H_+1           803_E_+2       —   —   —   —   0.3491   803_E_+2           CNTL   1.1%   0.4%   28.6%   0.4%   25.7%   42.4%   CNTL           CASE   0.9%   0.9%   24.0%   0.0%   26.0%   48.0%   CASE                                                                     962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2                                                                                                                             962_E_3   0.2697   0.4471   0.2848   0.1582   0.5166   0.2632   0.3556                         962_E_3           962_E_+2       0.3692   0.1179   0.1643   0.5854   0.1661   0.4283                         962_E_+2           962_G_4   —   —   0.1539                         0.2729   0.098   0.3311                         962_G_4           962_G_1       —   —   0.0742   0.2966   0.0975   0.1596                         962_G_1           962_G_2   —   —   —   —   0.5009   0.4053   0.4236                         962_G_2           962_G_6   —   —   —   —   —   0.1841   0.1991                         962_G_6           962_H_+2   —   —   —   —   —   —   0.2445                         962_H_+2           962_M_+2   —   —   —   —   —   —   —                         962_M_+2           962_P_−2   —   —   —   —   —   —   —   —   962_P_−2           962_Q_−1   —   —   —   —   —   —   —   —   962_Q_−1           962_S_−1   —   —   —   —   —   —   —   —   962_S_−1           962_U_1   —   —   —   —   —   —   —   —   962_U_1           962_U_2   —   —   —       —   —   —   —   962_U_2           962_V_−1   —   —   —   —   —   —   —   —   962_V_−1           962_V_+2   —           —   —   —   —   —   962_V_+2           962_Z_1       —   —   —   —   —   —   —   962_Z_1           CNTL   36.8%   12.5%   14.0%   25.2%   6.4%   21.7%   43.6%   12.4%   CNTL           CASE   30.0%   8.5%   8.2%   34.9%   8.7%   15.0%   36.5%   3.0%   CASE                                                                     962_P_−2   962_Q_−1   962_S_−1   962_U_1   962_U_2   962_V_−1   962_V_+2   962_Z_1                                                                             962_E_3   0.7001   0.7038                         0.3907   0.5306   0.1475   0.7456   0.5462   962_E_3           962_E_+2   0.2666   0.3534                         0.4799   0.2426   0.1067   0.5848   0.6605   962_E_+2           962_G_4   0.4604   0.484                         0.3027   0.366   0.3921   0.297   0.3495   962_G_4           962_G_1   0.1284   0.1732                         0.0626   0.1182   0.1849   0.2897   0.3231   962_G_1           962_G_2   0.9134   0.8569                         0.1854   0.766   0.5967   0.8865   0.8829   962_G_2           962_G_6   0.135   0.1258                         0.0962   0.2368                         0.2299   0.4163   962_G_6           962_H_+2   0.5986   0.6454                         0.5194   0.4206   0.4917   0.3688   0.6572   962_H_+2           962_M_+2                                                                                                                                                                                   962_M_+2           962_P_−2   1   0.9998                         0.9493   0.6173   0.7626   0.9745   0.9291   962_P_−2           962_Q_−1   —   1                         0.9707   0.7799   0.7163   0.9784   0.9584   962_Q_−1           962_S_−1   —   —                                                                                                                                       962_S_−1           962_U_1   —   —   —   0.5642   0.8007   0.4202   0.8658   0.729   962_U_1           962_U_2   —   —   —   —   0.4151   0.3504   0.8659   0.8125   962_U_2           962_V_−1   —   —   —   —   —   0.3829   0.6388   0.7466   962_V_−1           962_V_+2   —   —   —   —   —   —   1   0.8919   962_V_+2           962_Z_1   —   —   —   —   —   —   —   0.7114   962_Z_1           CNTL   24.6%   24.8%   10.9%   3.7%   25.0%   34.4%   4.5%   30.0%   CNTL           CASE   24.0%   24.5%   1.0%   4.9%   20.6%   29.4%   3.8%   32.1%   CASE                        
     [0392]               TABLE 35                       HAPLOTYPE ANALYSIS OF SPECIFIC IgE PHENOTYPE US POPULATION                                                                        845_R_1   845_R_−1   845_P_+1   845_K_1   845_K_−2   845_J_1   845_J_−1                                                                                                                     845_R_1   0.175                         0.097   0.0804                         0.1689   0.2609   845_R_1           845_R_−1       0.6822   0.1594   0.6501   0.9435   0.4122   0.3452   845_R_−1           845_P_+1   —   —                         0.0909   0.1551   0.1498   0.1668   845_P_+1           845_K_1   —   —   —   1   0.6613   0.1843   0.358   845_K_1           845_K_−2       —   —   —   0.8264   0.3347   0.4297   845_K_−2           845_J_1   —   —   —   —   —   0.2144   0.3497   845_J_1           845_J_−1       —   —   —       —   0.4212   845_J_−1           845_I_−1       —   —   —   —   —   —   845_I_−1           845_H_+1       —   —   —   —   —   —   845_H_+1           845_H_−1       —   —   —   —   —   —   845_H_−1           845_G_+1   —   —   —   —   —   —   —   845_G_+1           845_F_+1       —   —   —   —   —   —   845_F_+1           845_D_1       —   —   —   —   —   —   845_D_1           845_D_−1   —   —   —   —   —   —   —   845_D_−1           CNTL   17.1%   32.5%   6.5%   0.0%   32.5%   30.9%   36.4%   CNTL           CASE   6.3%   28.1%   18.8%   0.0%   28.6%   43.8%   28.1%   CASE                                                                 845_I_−1   845_H_+1   845_H_−1   845_G_+1   845_F_+1   845_D_1   845_D_−1                                                                         845_R_1   0.2989   0.4563   0.1511   0.3264   0.3726   0.2774   0.2491   845_R_1           845_R_−1   0.9851   0.3784   0.8511   0.7938   0.9446   0.7015   0.6007   845_R_−1           845_P_+1   0.197   0.1484   0.2216   0.1837   0.2313   0.1372   0.1265   845_P_+1           845_K_1   0.9047   0.2098   0.8964   0.506   0.7327   0.9344   0.3654   845_K_1           845_K_−2   0.6989   0.2679   0.9696   0.5982   0.8598   0.7101   0.6064   845_K_−2           845_J_1   0.3023   0.3171   0.2419   0.3491   0.4717   0.3253   0.3068   845_J_1           845_J_−1   0.6395   0.5232   0.6157   0.5865   0.7769   0.4739   0.549   845_J_−1           845_I_−1   1   0.6081   0.9805   0.7185   0.816   0.9895   0.6621   845_I_−1           845_H_+1   —   0.4562   0.4663   0.5249   0.7149   0.4445   0.4594   845_H_+1           845_H_−1   —   —   1   0.8316   0.9391   0.9825   0.6571   845_H_−1           845_G_+1   —   —   —   0.7705   0.8159   0.6574   0.5856   845_G_+1           845_F_+1   —   —   —   —   1   0.9598   0.6606   845_F_+1           845_D_1   —   —   —   —   —   1   0.4301   845_D_1           845_D_−1   —   —   —   —   —   —   0.3432   845_D_−1           CNTL   13.3%   20.1%   48.1%   13.2%   17.5%   0.7%   11.0%   CNTL           CASE   12.5%   12.5%   46.7%   9.4%   15.6%   0.0%   17.9%   CASE                                                                 847_K_1   847_J_+1   847_E_+1   847_D_−1   847_C_+1   847_A_2   847_A_1                                                                         847_K_1   0.7364   0.5688   0.5756   0.1052   0.2831   0.9369   0.9841   847_K_1           847_J_+1       0.4757   0.1843                         0.1836   0.1681   0.3925   847_J_+1           847_E_+1       —   0.3765   0.1293   0.3792   0.593   0.3756   847_E_+1           847_D_−1   —   —   —   0.0516   0.1028   0.1118   0.0505   847_D_−1           847_C_+1   —   —   —   —   0.2134   0.5643   0.3653   847_C_+1           847_A_2   —   —   —   —   —   0.7523   0.8675   847_A_2           847_A_1   —   —   —   —   —   —   1   847_A_1           CNTL   7.3%   8.4%   12.3%   17.6%   18.2%   9.1%   0.7%   CNTL           CASE   8.3%   2.8%   5.6%   3.3%   8.8%   11.1%   0.0%   CASE                                                     874_R_+1   874_S_+1   874_T_−1   874_V_−1                                                             874_R_+1   0.8215   0.6966   0.9496   0.8969   874_R_+1           874_S_+1   —   0.8308   0.7872   0.9389   874_S_+1           874_T_−1   —   —   0.6733   0.8809   874_T_−1           874_V_−1       —   —   1   874_V_−1           CNTL   37.0%   42.2%   48.1%   18.8%   CNTL           CASE   33.3%   46.2%   42.3%   19.2%   CASE                                                             803_K_3   803_K_2   803_I_1   803_I_−1   803_H_+1   803_E_+2                                                                     803_K_3   1   0.2217   0.3284   0.7941   0.8564   0.2885   803_K_3           803_K_2   —   0.1522                                               0.2229                         803_K_2           803_I_1   —   —   0.2596   0.2116   0.3967   0.3811   803_I_1           803_I_−1   —   —   —   1   0.9655   0.136   803_I_−1           803_H_+1   —   —   —   —   1   0.3741   803_H_+1           803_E_+2   —   —   —   —   —   0.1529   803_E_+2           CNTL   0.6%   0.0%   27.6%   0.0%   24.4%   47.4%   CNTL           CASE   0.0%   3.6%   39.3%   0.0%   25.0%   32.1%   CASE                                                                     962_E_3   962_E_+2   962_G_4   962_G_1   962_G_2   962_G_6   962_H_+2   962_M_+2                                                                                                                             962_E_3   0.305   0.2406   0.2585                         0.2389   0.3664   0.3253   0.6097   962_E_3           962_E_+2   —   0.7706   0.7148   0.26   0.6897   0.0917   0.2222   0.8358   962_E_+2           962_G_4   —   —   0.3748   0.1121   0.3078   0.2144   0.6699   0.389   962_G_4           962_G_1       —   —   0.0999   0.3587   0.2778   0.2425   0.3823   962_G_1           962_G_2   —   —   —   —   0.7414   0.6277   0.6815   0.8657   962_G_2           962_G_6   —   —   —   —   —   0.216   0.6615   0.6239   962_G_6           962_H_+2   —   —   —   —   —   —   0.5501   0.3982   962_H_+2           962_M_+2   —   —   —   —   —   —   —   0.5704   962_M_+2           962_P_−2   —   —   —   —   —   —   —   —   962_P_−2           962_Q_−1   —   —   —   —   —   —   —   —   962_Q_−1           962_S_−1   —   —   —   —   —   —   —   —   962_S_−1           962_U_1   —   —   —   —   —   —   —   —   962_U_1           962_U_2   —   —   —   —   —   —   —   —   962_U_2           962_V_−1       —   —   —   —   —   —   —   962_V_−1           962_V_+2       —   —   —   —   —   —   —   962_V_+2           962_Z_1   —   —   —   —   —   —   —   —   962_Z_1           CNTL   33.6%   13.0%   12.9%   30.8%   9.7%   17.7%   37.7%   13.2%   CNTL           CASE   43.3%   9.4%   6.3%   46.9%   6.3%   28.1%   31.3%   16.7%   CASE                                                                     962_P_−2   962_Q_−1   962_S_−1   962_U_1   962_U_2   962_V_−1   962_V_+2   962_Z_1                                                                             962_E_3   0.0714   0.121   0.7172   0.1596   0.0999   0.7343   0.5741   0.0682   962_E_3           962_E_+2   0.0908   0.1311   0.8874   0.8644   0.0896   0.8613   0.7766   0.1191   962_E_+2           962_G_4                                               0.4842   0.4509                         0.7467                         0.0531   962_G_4           962_G_1   0.0616                         0.398   0.1067                         0.4599   0.1584                         962_G_1           962_G_2   0.0905   0.1021   0.8738   0.7868   0.0725   0.6338   0.2843   0.1006   962_G_2           962_G_6   0.117   0.1176   0.6019   0.4484   0.1235   0.3756   0.5743   0.1   962_G_6           962_H_+2   0.2436   0.1996   0.4288   0.6756   0.1596   0.1278   0.7467   0.0525   962_H_+2           962_M_+2   0.0637   0.1021   0.5669   0.8508   0.0878   0.9423   0.8599   0.2111   962_M_+2           962_P_−2                         0.0791   0.1051   0.1038   0.0869   0.0677   0.0677   0.0514   962_P_−2           962_Q_−1   —                         0.1482   0.1022                                                                     0.0558   962_Q_−1           962_S_−1   —   —   1   0.9234   0.1333   0.9917   0.9384   0.22   962_S_−1           962_U_1   —   —   —   0.4864   0.0912   0.9104   0.8463                         962_U_1           962_U_2   —   —   —   —                                                                                           962_U_2           962_V_−1   —   —   —   —   —   1   0.1642   0.0526   962_V_−1           962_V_+2   —   —   —   —   —   —   1   0.0525   962_V_+2           962_Z_1   —   —   —   —   —   —   —                         962_Z_1           CNTL   22.4%   21.7%   12.2%   1.9%   21.7%   35.4%   4.7%   35.5%   CNTL           CASE   42.9%   40.0%   12.5%   3.6%   40.6%   36.7%   3.1%   15.6%   CASE                        
     [0393] All SNP combinations in Tables 33, 34, and 35 that demonstrated a significant difference (p≦0.05) in the distribution of frequencies of the four haplotypes between the cases and the control populations were further analyzed to identify individual haplotypes that were also significant. Table 36 presents the haplotypes that were significantly associated, at the 0.05 level of significance, with the Specific IgE phenotype. Haplotypes with higher allele frequency in the case population than in the control population acted as risk factors that increased the susceptibility to asthma. Haplotypes with lower allele frequencies in the case population than in the control population acted as protective factors that decreased the susceptibility to asthma. For Gene 845, two haplotypes were protective in the US population. They were haplotypes A/C (SNPs R1/R−1, p=0.0237) and A/G (SNPs R1/K−2, p=0.0268). Haplotypes G/C (SNPs R1/R−1, p=0.0308) and G/G (SNPs R1/K−2, p=0.0392) were susceptibility haplotypes in the US population. For Gene 847, two haplotypes were protective in the US population. They were haplotypes C/C (SNPs J+1/D−1, p=0.0409) and C/G (SNPs D−1/A1, p=0.0378). Haplotypes C/A (SNPs J+1/D−1, p=0.0113) and A/G (SNPs D−1/A1, p=0.0399) were susceptibility haplotypes in the US population. For Gene 962, seven haplotypes were susceptibility haplotypes in the combined population. They were haplotypes G/A (SNPs G4/G1, p=0.0175), G/G (SNPs G4/S−1, p=0.0066), A/G (SNPs G1/M+2, p=0.0107), A/A (SNPs G1/P−2, p=0.0054), A/A (SNPs G1/Q−1, p=0.0016), A/G (SNPs G1/S−1, p=0.0052) and ANT (SNPs G1/U2, p=0.004). The haplotype A/G (SNPs G4/G1, p=0.0211) was a protective haplotype in the combined population. Five haplotypes were susceptibility haplotypes in the UK population. They were G/A (SNPs G4/G1, p=0.0258), A/G (SNPs G1/M+2, p=0.0289), G/G (SNPs G1/S−1, p=0.02103), C/G (SNPs G6/S−1, p=0.0014) and C/C (SNPs G6/V−1, p=0.0084). Four haplotypes were protective haplotypes in the UK population. They were haplotypes G/C (SNPs G1/M+2, p=0.0171), G/C (SNPs G1/S−1, p=0.01065), C/C (SNPs G6/S−1, p=0.00239) and T/C (SNPs G6N-1, p=0.0085). Eight haplotypes were susceptibility haplotypes in the US population. They were haplotypes G/T (SNPs G4/U2, p=0.0446), A/A (SNPs G4/V+2, p=0.0433), ANA (SNPs G1/Q−1, p=0.003), A/T (SNPs G1/U2, p=0.0054), A/C (SNPs Q−1/V−1, p=0.0156), G/C (SNPs U1/Z1, p=0.0246), T/C (SNPs U2/V−1, p=0.0123) and T/G SNPs U2/V+2, p=0.0478). Four haplotypes were protective in the US population. They were haplotypes T/G (SNPs E3/G1, p=0.0118), T/C (SNPs Q−1/V−1, p=0.0123), G/T (SNPs Ul/Z1, p=0.0246) and C/C (SNPs U2/V−1, p=0.0225).  
                                   TABLE 36                           SNP                           COMBI-   HAPLO-   FREQUENCIES       P-       GENE   NATION   TYPE   CNTL   CASE   VALUE                                    Specific IgE Combined       US and UK                                     962   G4/G1   GA   0.208523   0.311853   0.0175       962   G4/G1   AG   0.071601   0.009531   0.0211       962   G4/S−1   GG   0.772436   0.886176   0.0066       962   G1/M+2   AG   0.231629   0.346667   0.0107       962   G1/P−2   AA   0.057605   0.15373   0.0054       962   G1/Q−1   AA   0.049187   0.157002   0.0016       962   G1/S−1   AG   0.23279   0.357599   0.0052       962   G1/U2   AT   0.052762   0.147695   0.004                 Specific IgE       UK Population                                     962   G4/G1   GA   0.175073   0.282626   0.0258       962   G1/M+2   AG   0.217702   0.329111   0.0289       962   G1/M+2   GC   0.089986   0.010015   0.0171       962   G1/S−1   GG   0.221485   0.339623   0.02103       962   G1/S−1   GC   0.079171   0   0.01065       962   G6/S−1   CG   0.681786   0.85033   0.0014       962   G6/S−1   CC   0.101659   0   0.00239       962   G6/V−1   CC   0.498551   0.660434   0.0084       962   G6/V−1   TC   0.157531   0.042045   0.0085                 Specific IgE       US Population                                     845   R1/R−1   GC   0.504855   0.71875   0.0308       845   R1/R−1   AC   0.17047   0   0.0237       845   R1/K−2   GG   0.504855   0.721154   0.0392       845   R1/K−2   AG   0.17047   0   0.0268       847   J+1/D−1   CA   0.738791   0.938697   0.0113       847   J+1/D−1   CC   0.176558   0.033525   0.0409       847   D−1/A1   AG   0.817323   0.966667   0.0399       847   D−1/A1   CG   0.175709   0.033333   0.0378       962   E3/G1   TG   0.383347   0.110692   0.0118       962   G4/U2   GT   0.191643   0.34375   0.0446       962   G4/V+2   AA   0   0.03125   0.0433       962   G1/Q−1   AA   0.042798   0.289956   0.003       962   G1/U2   AT   0.039558   0.279877   0.0054       962   Q−1/V−1   AC   0.217105   0.417425   0.0156       962   Q−1/V−1   TC   0.433253   0.197514   0.0123       962   U1/Z1   GT   0.3357   0.125   0.0164       962   U1/Z1   GC   0.64507   0.84375   0.0246       962   U2/V−1   TC   0.215811   0.40625   0.0123       962   U2/V−1   CC   0.431687   0.209559   0.0225       962   U2/V+2   TG   0.217236   0.375   0.0478                  
 
     Example 8  
     [0394] Genes Role in Asthma and Other Disorders  
     [0395] ADAM family proteins are known to interact with other cellular proteins. For example, the substrate of ADAM 19, NRG1, belongs to a group of growth factors (neuregulins) that are members of the epidermal growth factor family. The neuregulins participate in an array of biological effects that are mediated by the epidermal growth factor family of tyrosine kinase receptors. Data suggest that the proteolytically cleaved isoform of NRG1, NRG-β1, may induce the tyrosine phosphorylation of EGFR2 and EGFR3 in differentiated muscle cells (Shirakabe et. al., 2001,  J. Biol. Chem.  276(12):9352-8).  
     [0396] Epidermal growth factor receptor (EGFR1) plays a pivotal role in the maintenance and repair of epithelial tissue. Following injury in bronchial epithelium, EGFR1 is upregulated in response to ligands acting on it or through transactivation of the EGFR1 receptor. This results in the increased proliferation of cells and airway remodeling at the point of insult, leading to the repair of the bronchial epithelium (Polosa et. al., 1999,  Am. J. Respir. Cell Mol. Biol.  20:914-923; Holgate et. al., 1999,  Clin. Exp. Allergy  Suppl 2:90-95).  
     [0397] In asthma, the bronchial epithelium is highly abnormal, with structural changes involving separation of columnar cells from their basal attachments and functional changes that include increased expression and release of proinflammatory cytokines, growth factors, and mediator-generating enzymes. Beneath this damaged structure are the subepithelial myofibroblasts that have been activated to proliferate. This, in turn, causes excessive matrix deposition leading to abnormal thickening and increased density of the subepithelial basement membrane.  
     [0398] Immunocytochemical studies have shown that both TGF-β and EGFR1 are highly expressed at the area of injury and that parallel pathways could be operating in the repairing epithelial cells (Puddicombe et. al., 2000,  FASEB J.  14:1362-1374). EGFR1 stimulates epithelial repair and TGF-β regulates the production of profibrogenic growth factors and proinflammatory cytokines leading to extracellular matrix synthesis. As EGFR1 is involved in regulating a number of different stages of epithelial repair (survival, migration, proliferation and differentiation), any inhibitory effects that act on the receptor may cause the epithelium to be held in a “state of repair” (Holgate et. al., 1999,  Clin. Exp. Allergy  Suppl 2:90-95).  
     [0399] It is possible that variant ADAM family proteins induce the epithelium into a continuous “state of repair” by functioning improperly and failing to release their substrates (members of the neuregulin family) that serve as the ligand for EGFR1. This, in turn, may cause the observed increase in EGFR1 expression. Under these circumstances, the TGF-β pathway remains active, producing a continuous source of proinflammatory products as well as growth factors that drive airway wall remodeling causing bronchial hyperresponsiveness, a phenotype of asthma.  
     [0400] Gene 845—ADAM 19  
     [0401] Human ADAM19 (meltrin-β) is a member of the disintegrin and metalloprotease family and maps to chromosome 5q32-q33. The transcript is ˜7.0 Kb in size and is found to be expressed in many tissues including lung (Wei P, et. al., Biochem Biophys Res Comm 280: 744-755 (2001)). Studies of ADAM19 expressed in muscle and bone suggest that it plays a role in osteogenesis and myogenesis (Kurisaki T, et. al., Mech Dev 73:211-215 (1998)). Further, it is purported to heterodimerize with ADAM12 and may be involved in aggregation and fusion of cells with different surface phenotypes (Yamamato S, et. al., Immunology Today 20:278-284 (1999)). In the lung, ADAM19 can be involved in the sequestering of cells, such as myofibroblasts, to areas of inflammation. ADAM 19 is most closely related to the asthma-associated gene Gene 216 (U.S. patent application Ser. No. 09/834,597). Mutations in ADAM19 could modulate the function of the gene. Four single nucleotide polymorphisms (SNPs) have been identified within the open reading frame (ORF) of ADAM19 that cause amino acid changes. One of those SNPs, Gene845_J — 1 is strongly associated with the disease. This amino acid change, serine to glycine, resides within the catalytic domain between two conserved residues, leucine and tryptophan. It is possible that this amino acid change in ADAM19 may alter the functional capacity of the catalytic domain in the protein leading to the onset of asthma and other respiratory disorders.  
     [0402] Gene 847—Neuregulin 2  
     [0403] Human Neuregulin 2 (NRG2) is a member of the neuregulin family of growth and differentiation factors and maps to chromosome 5q23-q33. The transcript size is ˜3.0 Kb in size and there are six alternatively transcribed species which encode six protein isoforms. NRG2 is expressed in a limited number of tissues, which includes lung. The NRG2 isoforms interact with the Erbb family of receptors, inducing the growth and differentiation of epithelial, neuronal, glial and other types of cells (Ring H et. al., Human Genetics 104:326-334 (1999)). In the lung, NRG2 may be involved in the differentiation of cell types, such as lung fibroblasts to myofibroblasts, which are recruited to the site of inflammation and partake in airway remodeling. Two SNPs have been identified within the ORF of NRG2 that cause amino acid changes. These amino acid changes in NRG2 can alter the functional capacity of the protein leading to the onset of asthma and other respiratory disorders.  
     [0404] Gene 891—Neuregulin 1  
     [0405] Human Neuregulin 1 (NRG1) is a member of the neuregulin family of growth and differentiation factors and maps to chromosome 8p21-p12. The transcript size is ˜2.0 Kb and there are nine alternatively transcribed species that encode nine protein isoforms. All NRG1 isoforms interact with the Erbb family of tyrosine kinase transmembrane receptors. The interaction of NRG1 isoforms with Erbb receptors 2/3 induces the growth and differentiation of epithelial, neuronal, glial, and other types of cells. NRG1 is the substrate of ADAM19, which is proteolytically cleaved allowing NRG1 to interact with Erbb2/3. In the lung, NRG1 maybe involved in the differentiation of cell types, such as lung fibroblasts to myofibroblasts, which are recruited to the site of inflammation and partake in airway remodeling. NRG1 has also been shown to activate the JAK-STAT pathway and regulate lung epithelial cell proliferation (Liu and Kern,  Am. J. Respir. Mol. Biol.  27:306-13), thus implicating this gene in maintenance of epithelial integrity. It is possible that amino acid changes in NRG1 may alter the functional capacity of the protein leading to the onset of asthma and other respiratory disorders.  
     [0406] Gene 892—Endophilin1 (SH3GL2)  
     [0407] Human Endophilin 1 is a member of a family of proteins, which are adaptors that coordinate endocytosis, actin function and signaling cascades at the synapse and in non-neuronal cells. Endophilin 1 maps to 9p22. The transcript size is ˜2.7 Kb. ADAM9 and 15 have been shown to interact with Endophilin 1 by binding to the cytoplasmic domain of these proteins (Howard L, et. al., J Biol Chem 274:31693-31699 (1999)). Endophilin 1 may also interact with Gene216 at the cytoplasmic domain. The functional role of Endophilin 1 in non-neuronal cells is in membrane trafficking through clathrin-mediated endocytosis (Ringstad N, et. al., J Biol Chem [epub ahead of print] (2001)). This procedure is an important step in the process of modifying proteins en route to the membrane. It is possible that amino acid changes in Endophilin  1  may alter the functional capacity of the protein leading to the onset of asthma and other respiratory disorders.  
     [0408] Gene 893—Endophilin2 (SH3GL1)  
     [0409] Human Endophilin 2 is a member of a family of proteins, which are adaptors that coordinate endocytosis, actin function and signaling cascades at the synapse and in non-neuronal cells. Endophilin 2 maps to 19p13. The transcript size is ˜2.7 Kb. ADAM9 and 15 have been shown to interact with Endophilin 1 by binding to the cytoplasmic domain of these proteins (Howard L, et. al., J Biol Chem 274:31693-31699 (1999)). Endophilin 1 and 2 may interact with Gene216 at the cytoplasmic domain. The functional role of Endophilin 2 in non-neuronal cells, like Endophilin 1, is in membrane trafficking through clathrin-mediated endocytosis (Ringstad N, et. al.,  J Biol. Chem.  276(44): 40424-30 (2001)). This procedure is an important step in the process of modifying proteins en route to the membrane. It is possible that amino acid changes in Endophilin2 may alter the functional capacity of the protein leading to the onset of asthma and other respiratory disorders.  
     [0410] Gene 894—ADAM 3A  
     [0411] Human ADAM3a (cyritestin 1) is a member of the disintegrin and metalloprotease family and maps to chromosome 8p21-p12. The transcript is ˜2.6 Kb in size and is found to be expressed in testis (Adham I, et. al. DNA Cell Biol. 17: 161-168 (1998)). ADAM3a is involved in male fertility in mouse, however, in humans it appears to be non-functional (Grzmil P, et. al. Biochem J 357:551-556 (2001)). Based on the linkage analysis, ADAM3A and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0412] Gene 895—ADAM28  
     [0413] Human ADAM28 is a member of the disintegrin and metalloprotease family and maps to chromosome 8p21-p12. The transcript is 3.5 KB in size and highly expressed in epididymis and lymphocytes, and at lower levels in lung (Howard L, et. al., Biochem J 348:21-27 (2000)). Recently, ADAM28 has been shown to be a ligand for the leukocyte integrin alpha4beta1, implicating this gene in the interaction of lymphocytes with alpha4beta1-expressing leukocytes. Based on the linkage analysis, ADAM28 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0414] Gene 896—ADAM7  
     [0415] Human ADAM7 is a member of the disintegrin and metalloprotease family and maps to chromosome 8p21-p12. There are two transcripts 4.0 and 3.0 Kb in size, which are expressed in the caput region of the epididymis and in the anterior pituitary gonadotropes. No expression was detected in the twenty-six other tissues examined including lung (Cornwall G A, Hsia N, Endocrinology 138:4262-4272 (1997) and Lin Y C, et. al. Biol Reprod 65:944-95 (2001)). Based on the linkage analysis, ADAM7 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0416] Gene 897—ADAM9  
     [0417] Human ADAM9 is a member of the disintegrin and metalloprotease family and maps to chromosome 8q. The size of the transcript is ˜4.0 Kb and is expressed in many tissues including lung (Weskamp G, et. al., J Cell Biol 132:717-726 (1996)). ADAM9 has been shown to bind and proteolytically cleave the substrate heparin-binding EGF-like growth factor (HB-EGF). The secreted HB-EGF is a potent mitogen for a number of cell types and ADAM9 may act as a negative regulator (Izumi Y, et. al., EMBO 17:7260-7272 (1998)). Further, the cytoplasmic domain of ADAM9 has been shown to bind to Endophilin 1, which may modify the protein en route to its final destination at the cell surface. It is possible that amino acid changes in ADAM9 may alter the functional capacity of the protein leading to the onset of asthma and other respiratory disorders.  
     [0418] Gene 898—ADAM2  
     [0419] Human ADAM2 (Fertilin beta) is a member of the disintegrin and metalloprotease family and maps to chromosome 8p11.2. The size of the transcript is ˜2.8 Kb and is expressed in testis and prostate. ADAM2 is a cell adhesion molecule on the surface of mammalian sperm that participates in sperm-egg membrane binding (Evans J P, Bioessays 23:628-639 (2001)). Based on the linkage analysis, ADAM2 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0420] Gene 899—ADAM18  
     [0421] Human ADAM18 is a member of the disintegrin and metalloprotease family and maps to chromosome 8p11.2. Based on the linkage analysis, ADAM18 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0422] Gene 901—ADAMTS3  
     [0423] Human ADAMTS3 is an ADAM-related protein that possesses a disintegrin and metalloprotease domain as well as multiple copies of the thrombospondin motif. The gene maps to 4q13-q22 and the size of the transcript is ˜6.0 Kb. Like ADAMTS2, this gene has a limited expression profile: only expressed in adrenal gland, brain, breast, cervix, central nervous system, placenta, testis, and whole embryo. The enzyme encoded by this gene is similar in function to ADAMTS2; it excises the N-propeptide of type I, type II and type III procollagens (Tang B L, Int J Biochem Cell Biol 33:33-44 (2001)). Based on the linkage analysis, ADAMTS3 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0424] Gene 902—ADAMTS9  
     [0425] Human ADAMTS9 is an ADAM-related protein that possesses a disintegrin and metalloprotease domain as well as multiple copies of the thrombospondin motif. The gene maps to 3p14.2-p14.3 and the size of the transcript is ˜4.0 Kb. It is expressed at low levels in adult tissues; however, RT/PCR analysis indicated that it was expressed in ovary, heart, kidney, lung, placenta and in many fetal tissues (Clark M E, et. al. Genomics 67:343-350 (2000)). Based on the linkage analysis, ADAMTS9 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0426] Gene 903—Decysin  
     [0427] Human Decysin is a soluble ADAM-like protein that maps to chromosome 8p21-p12 between ADAM7 and 28. The transcript is ˜2.4 Kb in size and is expressed in limited number tissues that includes lung. Decysin is expressed in tissues where that demonstrate chronic antigen stimulation (Mueller C, et. al. J Exp Med 186:655-663 (1997)). The gene is expressed highly in mature dendritic cells that are localized to germinal centers. A continuous and high antigenic load in these sites may induce chronic interactions with dendritic and T-cells. Decysin maybe a key molecule in regulating the interaction of these cell types. Based on the linkage analysis, Decysin and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
     [0428] Gene 962—ADAMTS2  
     [0429] Human ADAMTS2 is an ADAM-related protein that possesses a disintegrin and metalloprotease domain as well as multiple copies of the thrombospondin motif. The gene maps to chromosome 5q35 and the size of the transcript is ˜4.0 Kb. It has a limited expression profile: only found in breast, heart, kidney and uterus and skin. The enzyme encoded by this gene excises the N-propeptide of type I, type II and type V procollagens. Inactivating mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder (Colige A, et. al. Am J Hum Genet 65:308-317 (1999) and Shi-Wu L, et. al. Biochem J 355:271-278 (2001)). Based on the linkage analysis, ADAMTS2 and variants thereof can be involved in the onset of asthma and other respiratory disorders.  
 
    
     
       
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                 SEQUENCE LISTING 
               
            
           
           
               
            
               
                 The patent application contains a lengthy “Sequence Listing” section. A copy of the “Sequence Listing” is available in electronic form from the USPTO 
               
               
                 web site (http://seqdata.uspto.gov/sequence.html?DocID=20040043021). An electronic copy of the “Sequence Listing” will also be available from the 
               
               
                 USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).