bluuebunny/crossref_metadata_2025 huggingface dataset:
Limb Girdle Muscular Dystrophy Type 2A (CAPN3): Mapping Using Allelic Association
Authors: Lonjou Christine , Collins Andrew , Beckmann Jacques , Allamand Valérie , Morton Newton
Published: April 2003

Recently a graphical study of linkage disequilibrium around the CAPN3 locus failed to refine the 1.3-Mb interval suggested by haplotype sharing. On the contrary, the Malecot model as implemented in the ALLASS program maps CAPN3 within 3 kb of its true location (23 kb from the locus midpoint), overcoming identified problems with small samples, interrelated sibships, and short duration.
No Evidence for Linkage of a Novel CA Repeat Polymorphism for Apoptosis Antigen 1 (APO-1 or Fas) with Type I Diabetes in a Caucasian Population
Authors: Sangthongpitag Kanda , Moore Katrina R. , Lapsys Naras M. , Bao Fei , Babu Sunanda R. , Fain Pamela R. , Verge Charles F.
Published: April 2003

A novel microsatellite marker was found within 48.5 kb of the Fas gene. The observed heterozygosity in 160 healthy unrelated controls was 0.78. There was no evidence of linkage to type I diabetes mellitus in 120 diabetic children using the transmission disequilibrium test.
Allele Frequencies in a Worldwide Survey of a CA Repeat in the First Intron of the CFTR Gene
Authors: Mateu Eva , Calafell Francesc , Bonné-Tamir Batsheva , Kidd Judith R. , Casals Teresa , Kidd Kenneth K. , Bertranpetit Jaume
Published: April 2003

A dinucleotide CA repeat within intron 1 of the CFTR gene has recently been identified. We have determined the allele frequencies of this polymorphism in samples from 18 populations covering all major geographical areas, with a total of 1,816 chromosomes. When considering allele distributions, African populations presented a wider range of alleles than other populations and also presented higher expected heterozygosities. Analysis of molecular variance showed that 8.04% of the genetic variance in this locus could be attributed to differences among populations. We concluded that the polymorphism in the CA repeat in intron 1 of the CFTR gene is highly informative in populations from all geographical regions of the world. Thus, it can be applied to family studies of unknown mutations causing cystic fibrosis (CF) and can provide valuable information for genetic counseling. Moreover, its analysis should be included in the haplotypic analysis of known CF mutations.
Variable Distribution of TFF2 (Spasmolysin) Alleles in Europeans Does Not Indicate Predisposition to Gastric Cancer
Authors: dos Santos Silva Elisabeth , Kayademir Tuncay , Regateiro Fernando , Machado José Carlos , Savas Sevtap , Dobosz Tadeusz , Blin Nikolaus , Gött Peter
Published: April 2003

Peptides belonging to the trefoil factor family (TFF) protect the gastrointestinal epithelia. Overexpression of TFFs was observed in pathological conditions such as gastritis, ulceration, metaplasia and neoplasia of the gastrointestinal tract. The aims of this work were to investigate the recently described TFF2 gene polymorphism in different European populations. DNA samples from blood of healthy individuals and gastric cancer patients were genotyped using the polymerase chain reaction. They were compared to a gastric cancer population. The results do not show any significant difference in allelic frequencies between gastric cancer patients and healthy individuals from Portugal. However, the frequency of the two alleles found varies considerably among Europeans.
Genomic Distribution and Gonadal mRNA Expression of Two Human Luteinizing Hormone Receptor Exon 1 Sequences in Random Populations
Authors: Tsai-Morris Chon Hwa , Geng Yi , Buczko Ellen , Dehejia Anindya , Dufau MariaL.
Published: April 2003

Exon 1 of the human luteinizing hormone receptor (LHR) gene coding region exhibits at least two forms of sequence heterogeneity between 37 and 60 bp, spanning the junction of the signal peptide and the amino terminus of the mature protein. The LHR 1 differs from the LHR 2 by the insertion of 6 bp in exon 1 but is of identical sequence in the 5′ flanking region. RFLP analysis of the two haplotypes within a random population of 63 individuals revealed allele frequencies of 0.37 and 0.63 for LHR 1 and LHR 2, respectively. 94% of the samples contained at least one LHR 2 allele, whereas only 68% contained the LHR 1 allele. No gender differences were observed, and both homozygotes and heterozygotes displayed apparently normal reproduction. Reverse-transcriptase polymerase chain-reaction analyses of LHR mRNA from testes and ovaries revealed that both haplotypes are transcribed in normal individuals, with no difference in tissue specific distribution. Thus, at least two functional polymorphic forms of exon 1 coding region of the same LHR gene are present in a random human population.
Identification in Portugal and Brazil of a mtDNA Lineage Containing a 9-bp Triplication of the Intergenic COII/tRNALys Region
Authors: Alves-Silva Juliana , Guimarães Pedro E.M. , Rocha Jorge , Pena Sérgio D.J. , Prado Vania F.
Published: April 2003

Although the deletion of one of the 9-bp repeats in region V of mitochondrial DNA is very common in Asians, Asian-derived populations and Africans, the triplication of the 9-bp segment was described only a few times, mostly on individuals from Asian origin. Here, we report for the first time the presence of the 9-bp triplication in Europeans. The triplication was initially found in one Brazilian individual. Sequencing of the hypervariable segments I (HVSI) and II (HVS2) of the control region and RFLP analysis of the coding region classified the mtDNA as belonging to the European haplogroup H. Since white Brazilians are predominantly of Portuguese descent, we screened 96 unrelated Northern Portuguese for the 9-bp triplication and found its presence in two of them (2.1%). One of these had an mtDNA haplotype identical to that of the Brazilian individual, while the other differed in a single base change in HVS2. The fact that the 9-bp triplication has reached polymorphic frequencies in Northern Portugal and that it has apparently differentiated into at least two lineages defined by the mutuation in HVS2 suggests that it probably occurred a long time ago.
A Novel Mutation (R271X) in the Myotubularin Gene Causes a Severe Miotubular Myopathy
Authors: De Luca Alessandro , Torrente Isabella , Mangino Massimo , Bertini Enrico , Dallapiccola Bruno , Novelli Giuseppe
Published: April 2003

The mutation is a C to T transition at nucleotide 811 of the MTM1 gene (OMIM 310400) leading to premature termination of translation at codon 271 of the myotubularin protein (R271X).
Absence of the Derived Allele at the DYS199 Locus in 3 NE Chinese Populations
Authors: Wang Bai-qiu , Fu Song-bin , Sun Yan-Yang , Huang Cheng-bin , Yang Huan-jie , Xue Ya-li , Wang Qi , Zhang Gui-yin , Li Pu
Published: April 2003

The allelic states of DYS199 locus were studied by allele-specific PCR. We found that all of the 107 samples chosen from three populations of northeast China had DYS199 C alleles. The result excluded the possibility that this mutation first identified in native American populations came from the three populations of northeast China.
Contribution of Interleukin 1β and KM Loci to Alopecia areata
Authors: Galbraith GillianM.P. , Palesch Yuko , Gore ElizabethA. , Pandey JanardanP.
Published: April 2003

Alopecia areata is a common skin disease in which proinflammatory cytokines such as IL-1β may play a pathogenic role. In this study, we examined the distribution of genotypes of an IL-1β single base change polymorphism at position +3953 in patients with alopecia areata. The distribution of immunoglobulin κ light chain (KM) genotypes was similarly examined. The data obtained showed that the IL-1β and KM loci act cooperatively to significantly increase susceptibility to alopecia areata.
Linkage Information Content of Polymorphic Genetic Markers
Authors: Guo Xiuqing , Elston RobertC.
Published: April 2003

The Polymorphism Information Content (PIC) value is often used to measure the informativeness of a genetic marker for linkage studies. The PIC value was first derived for the case of a rare dominant disease, when one of the parents is affected, and is a function of the particular mode of disease inheritance. We first generalize the definition of the PIC value in such a way that it does not depend on the mode of inheritance of the trait being studied, and then develop a Linkage Information Content (LIC) value to measure the informativeness of a marker about the identity-by-descent sharing status of particular types of pairs of relatives. Knowing the LIC value, it is possible to determine the effective number of fully informative pairs in a study when we have incomplete marker information.
Detection of the Most Common G6PD Gene Mutations in Chinese Using Amplification Refractory Mutation System
Authors: Du Chuan S. , Ren Xiaoqin , Chen Luming , Jiang Weiying , He Yongshu , Yang Ming
Published: April 2003

Glucose-6-phosphate dehydrogenase (G6PD) is the most common human enzymopathy. To date more than 122 mutations in the G6PD gene have been discovered, among which 12 point mutations are found in the Chinese. The 2 most common mutations, G1388A and G1376T, account for more than 50% of mutations representing various regions and ethnic groups in China. Setting up a simple and accurate method for detecting these mutations is not only useful for studying the frequency of the G6PD genotypes, but also for finding new mutations. The purpose of this study was to find a simple, inexpensive and accurate method for detecting these common mutations. The amplification refractory mutation system (ARMS) method was used in this study. Samples from 28 G6PD-deficient males were investigated. The natural and mismatched amplification and restriction enzyme digestion method was used as a standard method to evaluate the nature of the point mutations. Sixteen cases were found carrying the G1388A mutation and 12 the G1376T mutation. Fourteen cases of G1388A and 10 cases of G1376T were confirmed by ARMS. Four cases were not in concordance with the results obtained by the mismatched amplification-restriction enzyme digestion. These 4 cases were then judged by direct PCR sequencing at exon 12. The DNA sequencing data supported the results obtained by ARMS. Thus we concluded that the ARMS is a rapid, simple, inexpensive and accurate method for detecting the most common G6PD gene mutations among the Chinese.
Analysis of Estrogen Receptor Dinucleotide Polymorphism by Capillary Gel Electrophoresis with a Population Genetic Study in 180 Finns
Authors: Kunnas Tarja A. , Holmberg-Marttila Doris , Karhunen Pekka J.
Published: April 2003

We developed a suitable method for analysing dinucleotide repeats found in the upstream of human alpha-estrogen receptor (ER) gene by applying capillary electrophoresis and automatic analysis. This method omits the gel-casting step as well as difficult handling of long polyacrylamide sequencing gels. Use of radioactive materials is also avoided. Using this method, the frequency distribution of ER alleles, determined in 180 Finnish individuals showed two peaks at 12 and 14 repeats (166 and 168 bp) and also at 22 and 24 repeats (184 and 186 bp). The overall distribution of alleles seemed to be similar to that found among Italian and Japanese populations.
The LWb Blood Group as a Marker of Prehistoric Baltic Migrations and Admixture
Authors: Sistonen P. , Virtaranta-Knowles K. , Denisova R. , Kučinskas V. , Ambrasiene D. , Beckman L.
Published: April 2003

Archaeological findings and historical records indicate frequent migrations and exchange of genetic material between populations in the Baltic Sea area. However, there have so far been very few attempts to trace migrations in this area using genetic markers. We have studied the Baltic populations with respect to exceptional variations in the frequencies of the Landsteiner-Wiener (LW) blood group. The frequency of the uncommon LWb gene was high in the Balts, around 6% among Latvians and Lithuanians, very low among the other western Europeans (0–0.1%) and apparently absent in Asiatic and African populations. From the Baltic region of peak frequency there was a regular decline of LWb incidence (a descending cline) in the neighboring populations: 4.0% in the Estonians, 2.9% in the Finns, 2.2% in the Vologda Russians, and 2.0% in the Poles. Thus the distribution of LWb suggests considerable and extensive Baltic admixture, especially in the north and northeast direction. In Southern Sweden with an LWb frequency of 0.3%, the Baltic influence appeared slight, while in the population of the Swedish island Gotland in the middle of the Baltic Sea there was a significantly incrased LWb frequency of 1.0% compared with that of Western European countries. The distinction of codominantly inherited LW antigenic forms, LWa and LWb (previously Nea), is known to be due to a single base substitution. Based on our population data, it is plausible that the expansion of this point mutation occurred only once during human history. Furthermore, our data indicate that the expansion of the LWb mutation occurred in Balts and that LWb can be considered a ‘Baltic tribal marker’, its presence in other populations being an indicator of the degree of Baltic genetic influence.
Identification of a New Transthyretin Variant (Ile49) in Familial Amyloidotic Polyneuropathy Using Electrospray Ionization Mass Spectrometry and Nonisotopic RNase Cleavage Assay
Authors: Nakamura Masaaki , Yamashita Taro , Ando Yukio , Asl Kamran Hamidi , Tashima Kazuhiro , Ohlsson Per-Ingvar , Kususe Yukio , Benson Merrill D.
Published: April 2003

Mutation of the transthyretin (TTR) plasma protein and gene in a Japanese patient with amyloid polyneuropathy was investigated by electrospray ionization mass spectrometry (ESI-MS) and nonisotopic RNase cleavage assay (NIRCA), respectively. ESI-MS analysis showed normal TTR peaks and additionally a variant TTR with 12-dalton-higher molecular weight than normal TTR. NIRCA suggested that the mutation existed near either the 5′ or 3′ end of exon 3. Direct DNA sequencing revealed both a normal ACC (threonine) and a variant ATC (isoleucine) at codon 49, which was located near the 5′ end of exon 3. The molecular weight shift of this mutation was 12 D, consistent with the result of ESI-MS.
The Analysis of Parental Origin of Alleles May Detect Susceptibility Loci for Complex Disorders
Authors: Paterson Andrew D. , Naimark David M.J. , Petronis Arturas
Published: April 2003

The phenomenon of genomic imprinting describes the differential behavior of genes depending on their parental origin, and has been demonstrated in a few rare genetic disorders. In complex diseases, parent-of-origin effects have not been systematically studied, although there may be heuristic value in such an approach. Data from a genome scan performed using 356 affected sibling pair families with type 1 diabetes were examined looking for evidence of excess sharing of either maternal or paternal alleles. At the insulin gene (IDDM2), evidence for excess sharing of alleles transmitted from mothers was detected, which is consistent with transmission disequilibrium results published elsewhere. We also identified additional loci that demonstrate allele sharing predominantly from one parent: IDDM8 shows a paternal origin effect, IDDM10 shows a maternal effect, and a locus on chromosome 16q demonstrates a paternal effect. We have also evaluated these loci for confounding by differences in sex-specific meiotic recombination by performing linkage analysis using sex-specific genetic maps. The analysis of the parental origin of shared alleles from genome scans of complex disorders may provide additional evidence for linkage for known loci, help identify regions containing additional susceptibility loci, and assist the cloning of the genes involved.
Major Beta-Globin Gene Mutations in Eastern India and Their Associated Haplotypes
Authors: Bandyopadhyay Aditi , Bandyopadhyay Sanmay , Chowdhury Manju Dutta , Dasgupta Uma B.
Published: April 2003

324 alleles of the β-globin gene from unrelated thalassaemia patients native to the eastern region of India (mainly from the state of West Bengal) were analysed for β-globin gene mutations by the amplification refractory mutation system (ARMS). The major mutations that were detected are IVS-1 pos 5 (G–C), codon 26 (G–A) and codon 30 (G–C) with frequencies of 0.45, 0.33 and 0.05, respectively. Haplotype analysis revealed a very strong linkage disequilibrium of IVS-1 pos 5 (G–C) with one particular haplotype. HbE was found to be associated with two major haplotypes. Codon 30 (G–C) was associated with a haplotype that is the same as that found in the African population. Haplotype associated with codon 8/9 (+G) was the same as that found in northwest India. These findings have implications for the use of molecular diagnosis for genetic counselling and prenatal diagnosis of β-thalassaemia in this region.
Unsolved Problems in Genetic Epidemiology
Authors: Morton Newton E.
Published: April 2003

Genetic epidemiology faces six critical issues: its scope, genetic mapping, complex inheritance, population structure, nonmendelian genetics, and the internationalization of genetics. To solve these problems the scope must be broadened to include normal variation, although much of descriptive genetics will be lost to related sciences. Genetic mapping continues to play an essential role for positional cloning and chromosome architecture, which sequencing cannot replace. A large part of current effort is devoted to complex inheritance, requiring development of methods to pool multiple studies. The effect of population structure on forensic DNA identification appears to have been solved, but its effect for complex inheritance and genetic loads remains to be clarified. Populational analysis of non-Mendelian genetics has been largely neglected. The infrastructure of genetics must be internationalized if legal and ethical principles are to be supported and genetic epidemiology is to realise its potential.
Progressing from Eugenics to Human Genetics
Authors: Li C.C.
Published: April 2003

Eugenics, unlike science, involves decision making on various issues, and decision making involves the risk of making errors. This communication first clarifies the nature and seriousness of making errors known as type II in the statistical literature, i.e. the error of punishing a person when he is not guilty of the crime attributed to him. Eugenic laws in China and the eugenic movements in England and the United States are briefly reviewed. The explosive advances made in medical and population genetics in the last 40 years are replacing the conventional eugenics programs by new approaches. Modern genetic counseling has been introduced as the intermediate agent between the scientist and the family that needs advice. It is stressed that individual rights must be respected under all circumstances.
Haplotyping in Pedigrees via a Genetic Algorithm
Authors: Tapadar Pradip , Ghosh Saurabh , Majumder Partha P.
Published: April 2003

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist.
Gene Mapping in Isolated Populations: New Roles for Old Friends?
Authors: Jorde L.B. , Watkins W.S. , Kere J. , Nyman D. , Eriksson A.W.
Published: April 2003

Population isolates are increasingly being used in attempts to map genes underlying complex diseases. To further explore the utility of isolates for this purpose, we explore linkage disequilibrium patterns in polymorphisms from two regions (VWF and NF1) in three isolated populations from Finland. At the NF1 locus, the Finnish populations have greater pairwise disequilibrium than populations from Africa, Asia, or northern Europe. However, populations from ‘New Finland’ and ‘Old Finland’ do not differ in their disequilibrium levels at either the NF1 or the VWF locus. In addition, disequilibrium patterns and haplotype diversity do not differ between a sample from the Åland Islands, Finland, and a collection of outbred Centre d’Etude du Polymorphisme Humain families. These results show that linkage disequilibrium patterns sometimes differ among populations with different histories and founding dates, but some putative isolated populations may not significantly differ from larger admixed populations. We discuss factors that should be considered when using isolated populations in gene-mapping studies.
Mapping in the Sequencing Era
Authors: Collins Andrew
Published: April 2003

The present phase of the Human Genome Project is concerned with sequencing. The shift of emphasis has left an impression that mapping is in some sense complete or finished. On the contrary, faced with the challenges of mapping genes for complex traits and efforts to understand recombination and other biological processes, the need for accurate integrated metric maps is greater than ever. Furthermore, sequencing could be regarded as merely a way of improving the map, since the most useful ‘end product’ of the sequencing effort must be the annotated sequence that gives precise physical coordinates for markers and expressed sequences. Integration of both location and functional information, the latter provided by homology, expression and other functional studies, is the main target for the future.
Mapping Genes for Polygenic Disorders: Considerations for Study Design in the Complex Trait of Inflammatory Bowel Disease
Authors: Hampe Jochen , Wienker Thomas , Nürnberg Peter , Schreiber Stefan
Published: April 2003

While the methodology for the mapping of Mendelian disorders is well established, the practical and theoretical steps required for successful gene identification in a complex trait are still difficult to predict. A number of analytical models and simulations based on repetitive drawings from predefined statistical distributions are available. To supplement these analytical models, we developed an integrated simulation approach by directly simulating entire populations under a disease model based on epidemiological data. Random mating, nonoverlapping populations and the absence of differential fitness were assumed. Samples were drawn from these homogeneous and heterogeneous populations and analyzed with established analysis tools. We investigated the properties of linkage and association studies in inflammatory bowel disease – modeled as a six-locus polygenic disorder – as an example of this approach. In nonparametric linkage studies, lod scores varied widely, with the median required sample size depending on the locus-specific relative sibling risk. A fine mapping resolution <4 cM was found to require nonparametric lod scores >10. Family-based association studies (TDT test) and case-control studies showed a similar sensitivity and can identify risk loci in populations with moderate levels of linkage disequilibrium in sample sizes of 500–800 triplets. Case-control association studies were prone to false-positive results if applied in heterogeneous populations, with the false-positive rate increasing with sample size because population heterogeneity is detected with increasing power.
Allele-Specific Variation in the Gene Copy Number of Human Cytosine 5-Methyltransferase
Authors: Franchina Maria , Kay Peter H.
Published: April 2003

Previously, we have identified two alternate allelic forms of cytosine 5-methyltransferase, 5-MT I and 5-MT II, specified by polymorphic fragments of 1.5 and 1.1 kb, respectively. In the presence study, a 0.8-kb genomic probe was prepared which was confirmed to be included within the polymorphic fragments. The 0.8-kb probe hybridised with greater intensity to the 1.1-kb fragment than the 1.5-kb fragment. Densitometric analysis indicated that there is 1 copy of 5-MT associated with 5-MT I, whereas there may be 1–4 copies of the gene associated with the 5-MT II allele. Segregation studies demonstrated that the multiple copies of 5-MT II are inherited in a Mendelian fashion. These results allow novel approaches to investigating the underlying mechanisms of cytosine methylation and gene duplication.
Physical and cDNA Mapping in the DBH Region of Human Chromosome 9q34
Authors: Gilbert J.R. , Kumar A. , Newey S. , Rao N. , Ioannou P. , Qiu H. , Lin D. , Xu P. , Pettenati M.J. , Pericak-Vance M.A.
Published: April 2003

Chromosome 9q34 has been extensively studied and mapped due to the presence of known disease genes, principally tuberous sclerosis 1 (TSC1), in this region. During the course of our mapping of this region we constructed a 555-kb contig beginning approximately 50 kb proximal to the dopamine-β-hydroxylase (DBH) gene and extending, with one small deletion, distal to the D9S114 marker. The contig consists of 11 P1 clones, four PAC clones, one BAC clone and six cosmid clones and contains 27 new nonpolymorphic STSs. We have found the region to be unstable in P1, PAC and BAC cloning vehicles and have identified several deleted genomic clones. In addition, we have isolated and mapped the 3′ portions of three putative genes located within or immediately distal to the DBH gene, including one large gene that runs on the opposite strand to DBH and utilizes portions of two DBH exons. The genomic clones of the contig, cDNAs and new STSs will be useful reagents for the further study and mapping of this region.
Linkage of Hereditary Distal Myopathy with Desmin Accumulation to 2q
Authors: Saavedra-Matiz Carlos A. , Chapman Nicola H. , Wijsman Ellen M. , Horowitz Steven H. , Rosen Daniel R.
Published: April 2003

We are investigating the genetics of a large family with an autosomal dominant form of hereditary distal myopathy. This slowly progressive myopathy begins during early adulthood in the distal leg muscles, producing a gait disturbance. Cardiomyopathy is also present in most affected family members, manifesting itself as conduction block or congestive heart failure. Histologically, an accumulation of the protein, desmin, occurs in the subsarcolemmal spaces of myofibers. We have performed linkage analyses of this family, and have mapped the location of the gene causing the myopathy to human chromosome 2q33. The gene is within a 17-cM segment of chromosome 2q bounded by the DNA markers D2S2248 and D2S401. The best candidate gene for this myopathy is desmin.
Analysis of the SMN and NAIP Genes in Slovak Spinal Muscular Atrophy Patients
Authors: Zat’ková Andrea , Hahnen Eric , Wirth Brunhilde , Kádasi L’udovít
Published: April 2003

We identified homozygous absence of exon 7 of the telomeric copy of the survival motor neuron gene (telSMN) in 88.4% (38/43) of spinal muscular atrophy (SMA) patients from Slovakia. Additional deletions within the neuronal apoptosis inhibitory protein (NAIP) gene were found in 38.5% of type I, 12.5% of type II and never in type III SMA patients. Neither the SMN nor the NAIP gene was deleted in 81 healthy relatives and 25 controls tested. In one family, pseudodominant inheritance was identified. Both the type III SMA father and type II SMA son carried the homozygous deletion of the telSMN gene. One SMA I patient showed an SMN hybrid gene, probably created by intrachromosomal deletion. In two haploidentical type II SMA sibs, the telSMN exon 7 was absent on one chromosome, while the other carried an A→G transition 96 bp upstream of exon 7 of the telSMN gene, a potential disease-causing mutation in these patients.
Allelic Frequencies of FBN1 Gene Polymorphisms and Genetic Analysis of Italian Families with Marfan Syndrome
Authors: Mottes Monica , Mirandola Stefania , Rigatelli Federica , Zolezzi Francesca , Lisi Veronica , Gordon Derek , Pignatti Pier Franco
Published: April 2003

The fibrillin gene (FBN1) is the disease locus for Marfan syndrome. This disorder shows a high degree of clinical and allelic heterogeneity. Direct mutation screening has proven difficult and inefficient and at present cannot be utilized for routine analysis. In familial cases linkage analysis represents a useful tool for molecular diagnosis. We have determined the allelic frequencies of 5 polymorphic markers within the FBN1 locus in the Italian population and have successfully employed them for prenatal diagnosis and resolution of clinically equivocal cases.
Search for Coeliac Disease Susceptibility Loci on 7q11.23 Candidate Region: Absence of Association with the ELN17 Microsatellite Marker
Authors: Grillo Rita , Petronzelli Fiorella , Mora Barbara , Bonamico Margherita , Mazzilli Maria Cristina
Published: April 2003

The involvement of HLA genes in the susceptibility to coeliac disease (CD) has been well documented and represents the only consistently observed genetic feature of this multifactorial disease. In the present study, the search for new susceptibility genes has been devoted to a candidate region suggested by the association of CD with Williams syndrome (WS). This genetic disorder is due to a deletion in the 7q11.23 region that includes the elastin (ELN) gene. An increased prevalence of CD in WS patients has been previously reported and a case of CD-WS is also described in the present study. We used the ELN17 microsatellite marker mapped within the ELN gene to look for a possible contribution of this region to the susceptibility to CD. The analysis of 74 Italian CD families provided no evidence of association with the ELN17 marker.
Allelic Affinities between the F13A Common Gene Products Inferred by the Analysis of an (AAAG)n STR Polymorphism within the 5′ Untranslated Region
Authors: Prata M.J. , Miranda C. , Rocha J. , Amorim A.
Published: April 2003

Factor XIII a subunit (F13A) is the last enzyme in the blood coagulation cascade. It is characterized by extensive genetic polymorphism defined by 4 common alleles, F13A*1A, 1B, 2A and 2B and a few rare variants, some responsible for severe coagulation deficiencies. In order to infer the evolutionary affinities between the common F13A alleles we have applied PCR techniques to study, in a Northern Portuguese sample, a short tandem repeat polymorphism located within the 5′ untranslated region of the F13A gene. The analysis of the molecular heterogeneity within the F13A gene products revealed that the four biochemical variants shared very similar, truncated, distributions of STR alleles and showed no signs of predominant haplotypic associations. These findings seem to support both the inferences that intragenic recombination played an important role in the generation of molecular diversity within each of the four main F13A alleles and that all the four F13A alleles must be rather old. Molecular heterogeneity levels allowed the identification of 1B as the oldest F13A allelic state, and 2A as the most recently generated allele, but were not different enough to accurately track the divergence of alleles 1A and 2B. However, additional analysis of linkage disequilibrium patterns indicates that 1B→2B→1A→2A is the most likely evolutionary order of appearance of F13A main protein alleles, confirming and extending a previous hypothetical model inferred from their molecular features.
A Note on a Conditional-Likelihood Approach for Family-Based Association Studies of Candidate Genes
Authors: Hsu Li , Zhao Lue Ping , Aragaki Corinne
Published: April 2003

The family-based association study design is a variation of the case-control study design, where unaffected family members instead of unrelated subjects are sampled as controls. This variation is useful in assessing the effects of candidate genes on disease, because it avoids false associations caused by admixture of populations. A complication of this design is that because of an inherited genotypic correlation among family members, the genotypic distributions between cases and relative controls may be distorted by the ascertainment criteria of families, which could involve not only cases and relative controls, but also other relatives. Analyzing such data naively may lead to biased estimates of relative risk. In this note, we will discuss the consistency of a conditional-likelihood approach. We show analytically that maximum conditional-likelihood estimators are consistent for the true relative risks, if genotypes for family members are exchangeable under the sampling process, for example, sibling clusters. Besides being straightforward conceptually and computationally, this approach is robust to ascertainment bias and naturally accommodates genetic heterogeneity across families.
Prenatal Determination of a Variable Number of Tandem Repeats in Intron 40 of the von Willebrand Factor Gene from Maternal Peripheral Blood Using the Polymerase Chain Reaction
Authors: Ni Xingqun , Guo Jingyuan , Xia Jiahui , Li Luyun
Published: April 2003

To determine a fetal variable number of tandem repeats (VNTR) without using fetal tissues, we amplified the whole VNTR region in intron 40 of the von Willebrand factor gene from maternal peripheral blood by the polymerase chain reaction and then separated the amplified fragments by a nonhydratable polyacrylamide gel with an electrolyte gradient. After water elution from the gel, each preliminary product was amplified for the second time and then digested by Alu I restriction endonuclease. Then the VNTR was examined using a hydratable polyacrylamide gel with an electrolyte gradient. We successfully identified the fetal VNTR from 6 cases of 10 maternal peripheral blood samples and 2 cases of 6 maternal blood samples after parturition. This study might offer a theoretical basis for the noninvasive diagnosis of genetic disorders and identification of disputed paternity with common primers.
Linkage Analysis of Quantitative Trait Loci: Sib Pairs or Sibships?
Authors: Alcaïs Alexandre , Abel Laurent
Published: April 2003

Sib pair linkage studies are now widely used to investigate the genetic factors implicated in complex quantitative traits. To increase the power of these approaches, it has been proposed to select extremely discordant (ED) sib pairs which are expected to contain the highest linkage information. However, it is known that sibships of larger size contain more linkage information than independent sib pairs. In this paper we compare, in terms of power and cost considerations, the ED strategy, which uses information on sib pairs only, to the recently developed ‘Maximum Likelihood Binomial’ sibship-oriented method performed on the whole sibships from which the ED sib pairs have been extracted. We show that the use of these whole sibships is an efficient alternative to approaches focusing on ED sib pairs only.
A Study on the Degree of Relationship between Two Individuals
Authors: Montes Francisco , Plaza Mario , Ruá Enrique
Published: April 2003

The paper studies the likely degree of relationship between two individuals who could possibly be half sibs. The possible common ancestor was dead, which further complicated the problem. The model used was devised by Thompson [in Rao and Chakraborty (eds): Handbook of Statistics, North-Holland, Amsterdam, 1991] and establishes a correspondence between the possible degree of relationship and certain feasible probability distributions on the number of identical by descent genes. Two statistical approaches are considered: the classical one, in which the maximum likelihood estimation for the parameters of Thompson’s model are obtained, and the Bayesian one, in which the test of the hypothesis of half sibs is accompanied by a robustness study.
Gene-Environment Interaction and the Mapping of Complex Traits: Some Statistical Models and Their Implications
Authors: Guo Sun-Wei
Published: April 2003

The manifestation of many complex diseases or traits is very likely the result of an inextricable interplay of the biological and the environmental. Yet the role of environmental effect has traditionally been played down, for various reasons. In this paper, some simple statistical models that incorporate gene-environment interaction (GEI) have been proposed and their behavior and implications investigated. These implications concern the conditional independence assumption in likelihood calculation of pedigree data, the fine-tuning of the sib pair method for mapping quantitative traits, apportioning of disease or trait variation due to specific causes. In addition, they concern properties of gene mapping methods that do not take GEI into account, and they bring into question the utility of commonly used measures of genetic effects such as recurrence risk ratio for relative pairs, twin concordance rates, and heritability coefficients. In the presence of GEI, all these measures are functions not only of genetic effects and gene frequency, but also of environmental effects, the distribution of environmental factors in the population, and of GEI. Above all, these measures are all measures of familial aggregation, since they can be significant even in the absence of any genetic component of the disease. Thus their use as indicators of the genetic basis of complex diseases is cast into doubt.
A Complete Enumeration and Classification of Two-Locus Disease Models
Authors: Li Wentian , Reich Jens
Published: April 2003

There are 512 two-locus, two-allele, two-phenotype, fully penetrant disease models. Using the permutation between two alleles, between two loci, and between being affected and unaffected, one model can be considered to be equivalent to another model under the corresponding permutation. These permutations greatly reduce the number of two-locus models in the analysis of complex diseases. This paper determines the number of nonredundant two-locus models (which can be 102, 100, 96, 51, 50, or 58, depending on which permutations are used, and depending on whether zero-locus and single-locus models are excluded). Whenever possible, these nonredundant two-locus models are classified by their property. Besides the familiar features of multiplicative models (logical AND), heterogeneity models (logical OR), and threshold models, new classifications are added or expanded: modifying-effect models, logical XOR models, interference and negative interference models (neither dominant nor recessive), conditionally dominant/recessive models, missing lethal genotype models, and highly symmetric models. The following aspects of two-locus models are studied: the marginal penetrance tables at both loci, the expected joint identity-by-descent (IBD) probabilities, and the correlation between marginal IBD probabilities at the two loci. These studies are useful for linkage analyses using single-locus models while the underlying disease model is two-locus, and for correlation analyses using the linkage signals at different locations obtained by a single-locus model.
A Measure of Phase Ambiguity in Pairs of SNPs in the Presence ofLinkage Disequi librium
Authors: Hoh Josephine , Hodge Susan E.
Published: April 2003

The extent of haplotype ambiguity in a string of single-nucleotide polymorphisms (SNPs) was quantified by Hodge et al. [Nat Genet 1999;21:360]. In their measure, the level of ambiguity increases with increasing numbers of loci and as loci become more polymorphic. That work assumed linkage equilibrium (LE). However, linkage disequilibrium (LD) provides additional information about the haplotypes at a site, thereby diluting the level of ambiguity. The ambiguity vanishes altogether when LD reaches its maximum value. Here, we introduce the ambiguity measure, Φ, to allow for LD (between pairs of SNPs). We derive the formula Φ = 4x2x3 for ambiguity in individuals, where x1, x2, x3 and x4 are the probabilites of the A1A2, A1B2, B1A2 and B1B2 haplotypes, respectively, and w.l.o.g. x1x4 ≥ x2x3. Alternatively, Φ can be expressed in terms of the allele frequencies and the LD parameter δ. We also extend the formula to triads of two parents plus one child. We estimate our measure Φ for relevant SNPs in the published lipoprotein lipase (LPL) gene dataset [Clark et al., Am J Hum Genet 1998;63:595; Nickerson et al., Nat Genet 1998;19:233], obtaining values ranging from a low of 0 to a high of 0.11 among adjacent pairs of sites. In genome-wide LD studies to map common disease genes, a dense map of SNPs may be utilized to detect association between a marker and disease. Therefore, the measurement of ambiguity can potentially help investigators to determine a more efficient map, designed to minimize ambiguity and subsequent information loss.
The Human HNF-3 Genes: Cloning, Partial Sequence and Mutation Screening in Patients with Impaired Glucose Homeostasis
Authors: Navas M. Angeles , Vaisse Christian , Boger Stephanie , Heimesaat Markus , Kollee Louis A. , Stoffel Markus
Published: April 2003

Hepatocyte nuclear factors 3 (HNF-3α, -3β and -3γ) belong to an evolutionarily conserved family of transcription factors that are critical for diverse biological processes such as development, differentiation and metabolism. Gene expression studies have shown that HNF3 proteins are critical regulators of the early-onset type 2 diabetes genes HNF-1α, HNF-4α and IPF-1/PDX-1 (MODY3, 1 and 4, respectively) and of glucagon transcription and pancreatic α-cell function. In this study, we investigated whether genetic variation in the genes encoding HNF-3α, HNF-3β and HNF-3γ predisposes humans to hyperglycemic or hypoglycemic syndromes. In addition, we report the cloning and partial nucleotide sequence of the human HNF-3α, -3β and -3γ genes. Mutation screening included 96 subjects with type 2 diabetes mellitus, as well as one family with persistent neonatal hypoglycemia. No functional mutations were detected in the coding sequences of the three HNF-3 genes. Our results suggest that mutations in HNF-3 genes are not a common cause of type 2 diabetes mellitus. The data provided will facilitate genetic studies in other populations and will advance our understanding of the role HNF-3 plays in the development of diabetes mellitus and other metabolic disorders of glucose homeostasis.
The API2/MALT1 Fusion Product May Lead to Germinal Center B Cell Lymphomas by Suppression of Apoptosis
Authors: Stoffel Archontoula , Le Beau Michelle M.
Published: April 2003

Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT) represent a distinct clinicopathological entity that arises in a wide variety of extranodal sites. Genetically, MALT lymphomas are characterized by the t(11;18)(q21;q21). The genes involved in this translocation have been identified to be API2 on chromosome 11, which encodes an apoptotic inhibitor, and MALT1, a novel gene on chromosome 18. We identified the t(11;18)(q21;q21) by Southern blot analysis and reverse transcriptase PCR in 42% of a panel of extranodal MALT lymphomas. We also identified the breakpoints within the API2 and MALT1 genes in 7 patients, which revealed a consistent breakpoint after the third baculoviral inhibitor of apoptosis repeat domain within API2, and variable breakpoints in MALT1. We determined the API2/MALT1 fusion transcript in 2 cases by Northern blot analysis and also showed that MALT1 mRNA is constitutively expressed in a variety of human tissues. To understand the functional consequence of the translocation, we determined the pattern of expression of API2 and MALT1 through B lineage differentiation. API2 was expressed only in cell lines which correspond to mature B cells, whereas MALT1 mRNA was detectable in pre-B cells, mature B cells and plasma cells. These results suggest that fusion of MALT1 to API2 mediated by the t(11;18)(q21;q21) may result in an increased inhibition of germinal center B cell apoptosis and subsequent development of MALT lymphomas.
Epidemiology and Factor Analysis of Obesity, Type II Diabetes, Hypertension, and Dyslipidemia (Syndrome X) on the Island of Kosrae, Federated States of Micronesia
Authors: Shmulewitz Dvora , Auerbach Steven B. , Lehner Thomas , Blundell Maude L. , Winick Jeffrey D. , Youngman Linda D. , Skilling Vita , Heath Simon C. , Ott Jürg , Stoffel Markus , Breslow Jan L. , Friedman Jeffrey M.
Published: April 2003

Objectives: Obesity, type II diabetes, hypertension, and dyslipidemia are major causes of morbidity and mortality throughout the world. Though these disorders often cluster in individuals and families and are collectively known as syndrome X, the basis for this aggregation is not well understood. To further understand the pathogenesis of syndrome X, a comprehensive epidemiological study was undertaken on the Pacific Island of Kosrae, Federated States of Micronesia (FSM). Methods: The entire adult (>20 years of age) population of Kosrae underwent a clinical evaluation that included a questionnaire that noted the participants’ sex, family data including listing of biological parents, siblings, and children, smoking status, village of residence, age and health status. The medical evaluation included: anthropometric measures (weight, height, waist, hip), serum chemistries (leptin, fasting blood sugar (FBS), insulin, total cholesterol (TC), triglycerides (TG), and apolipoproteins B and A-I (apo B and apo A-I) and blood pressure (BP) measurements. Results: Obesity (BMI ≥35) was found in 24%, diabetes (FBS ≥126 or 2-hour oral glucose tolerance test ≥200) in 12%, hypertension (SBP ≥140 or DBP ≥90) in 17%, and dyslipidemia (TC ≥240 or TG ≥200 or apo B ≥120 or apo A-I ≤88) in 20% of the population. Significant covariate effects after multivariate analysis were as follows: sex affected the frequency of all four disorders, parity affected the frequency of dyslipidemia, smoking affected the frequency of obesity and diabetes, village of residence affected the frequency of obesity, hypertension, and dyslipidemia, and age affected the frequency of all four disorders. Factor analysis identified four independent factors that explained 73% of the total variance of the entire data set: factor 1 (weight, waist, leptin, insulin, and TG), factor 2 (TC, TG, apo B, apo A-I, and insulin), factor 3 (systolic and diastolic BP, FBS, waist and weight), and factor 4 (apo A-I, TG, leptin, and weight). Conclusions: This population-based study on the Island of Kosrae suggests that syndrome X is a composite of 4 independent factors: obesity with diabetes and hypertriglyceridemia, combined hyperlipidemia with diabetes, hypertension with obesity and diabetes, and increased HDL-low TG with thinness and high leptin. Further studies to identify the genetic components of these factors as well as the individual traits are under way.
Influence of Minor Increases in Plasma Catecholamines on Natural Killer Cell Activity
Authors: Kappel Mogens , Poulsen Troels D. , Galbo Henrik , Pedersen Bente K.
Published: April 2003

This study was designed to test the hypothesis that the modulations of the human immune system in relation to in vivo whole body hyperthermia may be ascribed to elevations in the plasma epinephrine and norepinephrine concentrations. In a single-blind, controlled, cross-over study, 8 healthy volunteers were selectively infused norepinephrine and epinephrine, respectively, for 1 h, in order to obtain twofold increases in the plasma concentrations of these hormones, thereby mimicking the increases seen during in vivo whole body hyperthermia. Epinephrine infusion increased baseline, interleukin-2 and interferon-α stimulated natural killer cell activity, and the percentage and concentration of cluster designation (CD)16+ cells, whereas the neutrophil and lymphocyte count or the CD3+, CD4+, CD8+, CD19+ and CD14+ cell subtypes were not influenced. Norepinephrine infusion did not cause any changes in these variables. It is concluded that epinephrine, but not norepinephrine, may be responsible for the hyperthermia-induced effects on natural killer cells.