Clinical trial NCT00005500: Collaborative Studies on the Genetics of Asthma (CSGA)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Asthma
Lung Diseases
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2000-05-26
Enrollment: 50
Sex: MALE
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE

Brief summary: To conduct molecular genetic studies in human pedigrees in order to identify the major genes responsible for asthma.

Detailed description: BACKGROUND:

Asthma is a respiratory disease characterized by variable airways obstruction, airways inflammation and bronchial hyperresponsiveness (BHR). There are recent increases in asthma mortality and prevalence in the US, especially in African-Americans. Multiple studies suggest that both genetic and environmental factors are important in asthma susceptibility.

The study was recommended by the Pulmonary Diseases Advisory Committee at its February 1991 meeting and given concept approval by the May 1991 National Heart, Lung, and Blood Advisory Council. The Request for Applications was released in October 1992.

DESIGN NARRATIVE:

The CSGA was composed of five centers (Johns Hopkins University, University of Chicago, University of Maryland, University of Minnesota, and a data coordinating center at Wake Forest). At each center, families were ascertained through two siblings with asthma. All family members were characterized with spirometry, bronchial responsiveness to methacholine or reversibility testing, skin-tests and questionnaire data. The initial genome screen was completed on the first 237 sib pairs from three racial groups (African-American, Caucasian and Hispanic), and genotyping on the remaining family members and families was completed before the study was renewed in 1997. Therefore, the initial aim of the CSGA to map susceptibility regions was completed, with detection of several novel chromosomal regions, and replication of several regions previously linked to associated phenotypes.

In order to determine the importance of these regions in asthma susceptibility and the impact of environmental rink factors, the investigators l) evaluated the evidence for linkage in the complete CSGA data using 2-point, multipoint and multilocus approaches for asthma and associated phenotypes (including BHR, total serum IgE and skin test reactivity to standardized allergens); 2) performed fine mapping studies of regions using additional genetic markers to obtain a \< 2 cM map; 3) identified candidate genes and novel sequence variants; and 4) characterized a patient population with asthma to study identified variants with respect to asthma severity and bronchial inflammation. These studies allowed identification of asthma susceptibility genes and their variants, interactions with other genes and environmental risk factors, as well as provided insight for the development of improved treatment and ultimate prevention of asthma.

Eligibility criteria: No eligibility criteria

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Johns Hopkins University
name: Terri Beatty
affiliation: University of Maryland
name: Eugene Bleecker
affiliation: University of Minnesota
name: Malcolm Blumenthal
affiliation: University of Chicago
name: Carole Ober
affiliation: Wake Forest University
name: Stephen Rich
References:
citation: Bleecker ER, Postma DS, Meyers DA. Genetic susceptibility to asthma in a changing environment. Ciba Found Symp. 1997;206:90-9; discussion 99-105, 106-10. doi: 10.1002/9780470515334.ch6.
citation: A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet. 1997 Apr;15(4):389-92. doi: 10.1038/ng0497-389.
citation: Marsh DG. Approaches toward the genetic analysis of complex traits: asthma and atopy. Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 2):S133-8. doi: 10.1164/ajrccm.156.4.12tac11.
citation: Blumenthal MN, Rich SS, King R, Weber J. Approaches and issues in defining asthma and associated phenotypes map to chromosome susceptibility areas in large Minnesota families. The Collaborative Study for the Genetics of Asthma (CSGA). Clin Exp Allergy. 1998 Apr;28 Suppl 1:51-5; discussion 65-6. doi: 10.1046/j.1365-2222.1998.0280s1051.x.
citation: Hizawa N, Collins G, Rafnar T, Huang SK, Duffy DL, Weber JL, Freidhoff LR, Ehrlich E, Marsh DG, Beaty TH, Barnes KC. Linkage analysis of Dermatophagoides pteronyssinus-specific IgE responsiveness with polymorphic markers on chromosome 6p21 (HLA-D region) in Caucasian families by the transmission/disequilibrium test. Collaborative Study on the Genetics of Asthma (CSGA). J Allergy Clin Immunol. 1998 Sep;102(3):443-8. doi: 10.1016/s0091-6749(98)70133-2.
citation: Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B, Gidley H, Kurtz B, Lee J, Nance M, Pettersson A, Prescott J, Richardson A, Schlenker E, Summerhill E, Willadsen S, Parry R. Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet. 1998 Sep;7(9):1393-8. doi: 10.1093/hmg/7.9.1393.
citation: Mathias RA, Freidhoff LR, Blumenthal MN, Meyers DA, Lester L, King R, Xu JF, Solway J, Barnes KC, Pierce J, Stine OC, Togias A, Oetting W, Marshik PL, Hetmanski JB, Huang SK, Ehrlich E, Dunston GM, Malveaux F, Banks-Schlegel S, Cox NJ, Bleecker E, Ober C, Beaty TH, Rich SS; CSGA (Collaborative Study of the Genetics of Asthma). Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families. Genet Epidemiol. 2001 Apr;20(3):340-55. doi: 10.1002/gepi.5.
citation: Barnes KC, Freidhoff LR, Horowitz EM, Mathias RA, Mulkern DM, Bonacum JT, Goldman MH, Polito AJ, Saini SS, Marsh DG, Beaty TH, Togias A. Physician-derived asthma diagnoses made on the basis of questionnaire data are in good agreement with interview-based diagnoses and are not affected by objective tests. J Allergy Clin Immunol. 1999 Oct;104(4 Pt 1):791-6. doi: 10.1016/s0091-6749(99)70289-7.
citation: Xu J, Meyers DA, Ober C, Blumenthal MN, Mellen B, Barnes KC, King RA, Lester LA, Howard TD, Solway J, Langefeld CD, Beaty TH, Rich SS, Bleecker ER, Cox NJ; Collaborative Study on the Genetics of Asthma. Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am J Hum Genet. 2001 Jun;68(6):1437-46. doi: 10.1086/320589. Epub 2001 May 10.
citation: Langefeld CD, Davis CC, Brown WM. Nonparametric linkage regression. I: Combined Caucasian CSGA and German genome scans for asthma. Genet Epidemiol. 2001;21 Suppl 1:S136-41. doi: 10.1002/gepi.2001.21.s1.s136.
citation: Davis CC, Brown WM, Lange EM, Rich SS, Langefeld CD. Nonparametric linkage regression. II: Identification of influential pedigrees in tests for linkage. Genet Epidemiol. 2001;21 Suppl 1:S123-9. doi: 10.1002/gepi.2001.21.s1.s123.
citation: Meyers DA, Wjst M, Ober C. Description of three data sets: Collaborative Study on the Genetics of Asthma (CSGA), the German Affected-Sib-Pair Study, and the Hutterites of South Dakota. Genet Epidemiol. 2001;21 Suppl 1:S4-8. doi: 10.1002/gepi.2001.21.s1.s4.
citation: Marsh DG. Approaches toward the genetic analysis of complex traits: asthma and atopy. Allergy. 1999 Mar;54(3):198-205. doi: 10.1034/j.1398-9995.1999.00090.x.
citation: Nickel RG, Saitta FP, Freidhoff LR, Yu XY, Ehrlich E, Barnes KC, Beaty T, Huang SK. Positional candidate gene approach and functional genomics strategy in atopy gene discovery. Int Arch Allergy Immunol. 1999 Feb-Apr;118(2-4):282-4. doi: 10.1159/000024100.
citation: Ober C, Leavitt SA, Tsalenko A, Howard TD, Hoki DM, Daniel R, Newman DL, Wu X, Parry R, Lester LA, Solway J, Blumenthal M, King RA, Xu J, Meyers DA, Bleecker ER, Cox NJ. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet. 2000 Feb;66(2):517-26. doi: 10.1086/302781.
citation: Howard TD, Meyers DA, Bleecker ER. Mapping susceptibility genes for asthma and allergy. J Allergy Clin Immunol. 2000 Feb;105(2 Pt 2):S477-81. doi: 10.1016/s0091-6749(00)90046-0.
citation: Howard TD, Bleecker ER, Stine OC. Fluorescent allele-specific PCR (FAS-PCR) improves the reliability of single nucleotide polymorphism screening. Biotechniques. 1999 Mar;26(3):380-1. doi: 10.2144/99263bm01. No abstract available.
citation: Stine OC, Xu J, Meyers DA, Bleecker ER. Approaches to fine mapping in asthma. Clin Exp Allergy. 1998 Apr;28 Suppl 1:98-100; discussion 108-10. doi: 10.1046/j.1365-2222.1998.0280s1098.x. No abstract available.
citation: Ober C. Susceptibility genes in asthma and allergy. Curr Allergy Asthma Rep. 2001 Mar;1(2):174-9. doi: 10.1007/s11882-001-0085-4.
citation: Ober C, Abney M, McPeek MS. The genetic dissection of complex traits in a founder population. Am J Hum Genet. 2001 Nov;69(5):1068-79. doi: 10.1086/324025. Epub 2001 Oct 3.
citation: Wu X, Di Rienzo A, Ober C. A population genetics study of single nucleotide polymorphisms in the interleukin 4 receptor alpha (IL4RA) gene. Genes Immun. 2001 May;2(3):128-34. doi: 10.1038/sj.gene.6363746.
citation: Abney M, McPeek MS, Ober C. Broad and narrow heritabilities of quantitative traits in a founder population. Am J Hum Genet. 2001 May;68(5):1302-7. doi: 10.1086/320112. Epub 2001 Apr 10.
citation: Ober C, Tsalenko A, Parry R, Cox NJ. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet. 2000 Nov;67(5):1154-62. doi: 10.1016/S0002-9297(07)62946-2. Epub 2000 Oct 5.
citation: Summerhill E, Leavitt SA, Gidley H, Parry R, Solway J, Ober C. beta(2)-adrenergic receptor Arg16/Arg16 genotype is associated with reduced lung function, but not with asthma, in the Hutterites. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):599-602. doi: 10.1164/ajrccm.162.2.9910108.
citation: Donfack J, Tsalenko A, Hoki DM, Parry R, Solway J, Lester LA, Ober C. HLA-DRB1*01 alleles are associated with sensitization to cockroach allergens. J Allergy Clin Immunol. 2000 May;105(5):960-6. doi: 10.1067/mai.2000.106926.
citation: Abney M, McPeek MS, Ober C. Estimation of variance components of quantitative traits in inbred populations. Am J Hum Genet. 2000 Feb;66(2):629-50. doi: 10.1086/302759.
citation: Ober C, Tsalenko A, Willadsen S, Newman D, Daniel R, Wu X, Andal J, Hoki D, Schneider D, True K, Schou C, Parry R, Cox N. Genome-wide screen for atopy susceptibility alleles in the Hutterites. Clin Exp Allergy. 1999 Dec;29 Suppl 4:11-5.
citation: Blumenthal MM. What we know about the genetics of asthma at the beginning of the 21st century. Clin Rev Allergy Immunol. 2002 Feb;22(1):11-31. doi: 10.1007/s12016-002-0003-0.
citation: Donfack J, Kogut P, Forsythe S, Solway J, Ober C. Sequence variation in the promoter region of the cholinergic receptor muscarinic 3 gene and asthma and atopy. J Allergy Clin Immunol. 2003 Mar;111(3):527-32. doi: 10.1067/mai.2003.71.
citation: Huang SK, Mathias RA, Ehrlich E, Plunkett B, Liu X, Cutting GR, Wang XJ, Li XD, Togias A, Barnes KC, Malveaux F, Rich S, Mellen B, Lange E, Beaty TH; Comparative Study on the Genetics of Asthma. Evidence for asthma susceptibility genes on chromosome 11 in an African-American population. Hum Genet. 2003 Jul;113(1):71-5. doi: 10.1007/s00439-003-0934-4. Epub 2003 Mar 27.
citation: Hsu FC, Liang KY, Beaty TH. Multipoint linkage disequilibrium mapping approach: incorporating evidence of linkage and linkage disequilibrium from unlinked region. Genet Epidemiol. 2003 Jul;25(1):1-13. doi: 10.1002/gepi.10241.
citation: Colilla S, Nicolae D, Pluzhnikov A, Blumenthal MN, Beaty TH, Bleecker ER, Lange EM, Rich SS, Meyers DA, Ober C, Cox NJ; Collaborative Study for the Genetics of Asthma. Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol. 2003 Apr;111(4):840-6. doi: 10.1067/mai.2003.170.
citation: Blumenthal MN, Langefeld CD, Beaty TH, Bleecker ER, Ober C, Lester L, Lange E, Barnes KC, Wolf R, King RA, Solway J, Oetting W, Meyers DA, Rich SS. A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma. Hum Genet. 2004 Jan;114(2):157-64. doi: 10.1007/s00439-003-1030-5. Epub 2003 Oct 25.
citation: Lester LA, Rich SS, Blumenthal MN, Togias A, Murphy S, Malveaux F, Miller ME, Dunston GM, Solway J, Wolf RL, Samet JM, Marsh DG, Meyers DA, Ober C, Bleecker ER; Collaborative Study on the Genetics of Asthma. Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma. J Allergy Clin Immunol. 2001 Sep;108(3):357-62. doi: 10.1067/mai.2001.117796.
citation: Liang KY, Hsu FC, Beaty TH. Multipoint linkage disequilibrium mapping for complex diseases. Genet Epidemiol. 2003 Dec;25(4):285-92. doi: 10.1002/gepi.10271.
citation: Blumenthal MN, Ober C, Beaty TH, Bleecker ER, Langefeld CD, King RA, Lester L, Cox N, Barnes K, Togias A, Mathias R, Meyers DA, Oetting W, Rich SS; CSGA. Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA). Genes Immun. 2004 May;5(3):226-31. doi: 10.1038/sj.gene.6364063.
citation: Blumenthal MN, Langefeld CD, Barnes KC, Ober C, Meyers DA, King RA, Beaty TH, Beck SR, Bleecker ER, Rich SS; Collaborative Study on the Genetics of Asthma. A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity. J Allergy Clin Immunol. 2006 Jan;117(1):79-85. doi: 10.1016/j.jaci.2005.09.038.