Asthma and lower airway disease
A genome-wide association study on African-ancestry populations for asthma

https://doi.org/10.1016/j.jaci.2009.08.031Get rights and content

Background

Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.

Objectives

We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma.

Methods

We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore–Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.

Results

A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10−5 in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the α-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 × 10−6); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 × 10−6); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated.

Conclusions

This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Section snippets

Sample description

We analyzed 498 asthmatic cases and 500 nonasthmatic control subjects from the Baltimore–Washington, DC, metropolitan area who self-reported as being of African American ethnicity. These subjects comprised the GRAAD consortium and represent 8 separate, National Institutes of Health–funded studies of asthma in pediatric and adult African American populations, plus 1 study on healthy African Americans. Because asthma is often characterized by onset during childhood, there was a deliberate

Results

Admixture analysis revealed ancestry misclassification for 7 of the African American subjects, and 18 subjects from an ethnically mixed family from Barbados were also excluded from subsequent analysis. Additionally, samples were dropped based on quality control analysis of familial relationships (n = 53) and Mendelian inconsistencies (n = 13). Fourteen samples in the African American group and 1 in the African Caribbean group revealed sex discrepancies compared with clinical records. Among all

Discussion

In this article we report the first GWAS for asthma focused on populations of African descent. Using 2 independent sets of samples, an African American case-control group from Baltimore–Washington, DC (n = 935), and 163 African Caribbean families from Barbados (n = 929), we have identified 3 genes as associated with asthma, each of which are biologically relevant to asthma pathology. However, these findings must be interpreted with caution because of limitations of sample size and the

References (64)

  • G.H. Koppelman et al.

    Genome-wide search for atopy susceptibility genes in Dutch families with asthma

    J Allergy Clin Immunol

    (2002)
  • J.W. Lomasney et al.

    Molecular cloning and expression of the cDNA for the alpha 1A-adrenergic receptor. The gene for which is located on human chromosome 5

    J Biol Chem

    (1991)
  • Z.W. Hu et al.

    Alpha1 adrenergic receptors activate phosphatidylinositol 3-kinase in human vascular smooth muscle cells. Role in mitogenesis

    J Biol Chem

    (1996)
  • N.R. Cashman et al.

    Cellular isoform of the scrapie agent protein participates in lymphocyte activation

    Cell

    (1990)
  • B.H. Kim et al.

    The cellular prion protein (PrPC) prevents apoptotic neuronal cell death and mitochondrial dysfunction induced by serum deprivation

    Brain Res Mol Brain Res

    (2004)
  • R. Li et al.

    The expression and potential function of cellular prion protein in human lymphocytes

    Cell Immunol

    (2001)
  • J.E. McCormack et al.

    PRNP contains both intronic and upstream regulatory regions that may influence susceptibility to Creutzfeldt-Jakob Disease

    Gene

    (2002)
  • E. Zagha et al.

    DPP10 modulates Kv4-mediated A-type potassium channels

    J Biol Chem

    (2005)
  • X. Ren et al.

    Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels

    Mol Cell Neurosci

    (2005)
  • I.P. Gorlov et al.

    Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms

    Am J Hum Genet

    (2008)
  • P.M. Sleiman et al.

    ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry

    J Allergy Clin Immunol

    (2008)
  • J.E. Moorman et al.

    National surveillance for asthma—United States, 1980-2004

    MMWR Surveill Summ

    (2007)
  • S.E. Daniels et al.

    A genome-wide search for quantitative trait loci underlying asthma

    Nature

    (1996)
  • The Collaborative Study on the Genetics of Asthma: a genome-wide search for asthma susceptibility loci in ethnically diverse populations

    Nat Genet

    (1997)
  • C. Ober et al.

    Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma

    Hum Mol Genet

    (1998)
  • G. Malerba et al.

    Candidate genes and a genome-wide search in Italian families with atopic asthmatic children

    Clin Exp Allergy

    (1999)
  • M. Wjst et al.

    A genome-wide search for linkage to asthma. German Asthma Genetics Group

    Genomics

    (1999)
  • M.H. Dizier et al.

    Genome screen for asthma and related phenotypes in the French EGEA study

    Am J Respir Crit Care Med

    (2000)
  • T. Laitinen et al.

    A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population

    Nat Genet

    (2001)
  • P. Van Eerdewegh et al.

    Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

    Nature

    (2002)
  • M.F. Moffatt et al.

    Genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma

    Nature

    (2007)
  • C. Ober et al.

    Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function

    N Engl J Med

    (2008)
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    Supported by National Institutes of Health grants HL087699, HL49612, AI50024, AI44840, HL075417, HL072433, AI41040, ES09606, HL072433, and RR03048 and US Environmental Protection Agency grant 83213901, and NIGMS grant S06GM08015. The genome-wide genotyping of the European study was funded by the Wellcome Trust, the Medical Research Council, the French Ministry of Higher Education and Research, the German Ministry of Education and Research (BMBF), the National Genome Research Network (NGFN), the National Institutes of Health (National Human Genome Research Institute and National Heart, Lung, and Blood Institute; G. R. A.), and the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community). K. C. B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. R. A. M. was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

    Disclosure of potential conflict of interest: R. A. Mathias, L. Gao, P. Gao, C. M. Ongaco, K. N. Hetrick, K. F. Doheny, E. W. Pugh, A. F. Scott I. Ruczinski, T. H. Beaty, and K. C. Barnes have received research support from the National Institutes of Health. N. N. Hansel has received research support from Pfizer. N. F. Adkinson has equity ownership in AllerQuest LLC, has received research support from the National Institutes of Health, and has provided expert testimony on the topic of drug hypersensitivity. M. C. Liu is a consultant for the Novartis Advisory Board and has received research support from Pfizer, Centocor, and Novartis. J. Ford is a consultant for GlaxoSmithKline and has received research support from the National Institutes of Health and the Centers for Medicare and Medicaid Services. B. A. Raby is the Section Editor for Up to Date and is an in-house lecturer for Novartis Pharmaceuticals. S. T. Weiss has received research support from Genentech. M. Kabesch has financial arrangements with Roxall, Glaxo Wellcome, Novartis, Sanofi Aventis, and Allergopharma and has received research support from DFG, BMBF, and the European Union. G. Abecasis has received research support from GlaxoSmithKline and the National Institutes of Health. The rest of the authors have declared they have no conflict of interest.

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