A genome-wide association study on African-ancestry populations for asthma

Rasika A. Mathias, ScDa, Audrey V. Grant, PhDb, Nicholas Rafaels, MSb, Tracey Hand, MSb, Li Gao, MD, PhDb, Candelaria Vergara, MScb, Yuhjung J. Tsai, MDb, Mao Yang, MSb, Monica Campbell, BSb, Cassandra Fosterb, Peisong Gao, MD, PhDb, A. Togias, MDb, Nadia N. Hansel, MD, MPHc, Gregory Diette, MDc, N. Franklin Adkinson, MDb, Mark C. Liu, MDc, Mezbah Faruque, MD, PhDd, Georgia M. Dunston, PhDd, Harold R. Watson, MDe, Michael B. Bracken, PhDf, Josephine Hoh, PhDf, Pissamai Maul, RNe, Trevor Maul, RNe, Anne E. Jedlicka, MSg, Tanda Murray, MSg, Jacqueline B. Hetmanski, MSg, Roxann Ashworth, MHSh, Chrissie M. Ongaco, BSh, Kurt N. Hetrick, MSh, Kimberly F. Doheny, PhDh, Elizabeth W. Pugh, PhD, MPHh, Charles N. Rotimi, PhDo, Jean Ford, MDg, Celeste Eng, BSi, Esteban G. Burchard, MDi, Patrick M.A. Sleiman, PhDj, Hakon Hakonarson, MD, PhDj, Erick Forno, MDk, Benjamin A. Raby, MDk, Scott T. Weiss, MDk, Alan F. Scott, PhDh, Michael Kabesch, MDl, Liming Liang, MSm, Gonçalo Abecasis, PhDm, Miriam F. Moffatt, PhDn, William O.C. Cookson, MDn, Ingo Ruczinski, PhDo, Terri H. Beaty, PhDg, Kathleen C. Barnes, PhDb c g

Received 24 June 2009; received in revised form 6 August 2009; accepted 21 August 2009. published online 12 November 2009.

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.

Key words: Asthma, genome-wide association study, ADRA1B, PRNP, DPP10, African ancestry, ethnicity, polymorphism, genetic association

a Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Md

b Division of Allergy and Clinical Immunology, Department of Medicine, the Johns Hopkins University, Baltimore, Md

c Pulmonary and Critical Care Medicine, Department of Medicine, the Johns Hopkins University, Baltimore, Md

d National Human Genome Center at Howard University, Washington, DC

e University of the West Indies, Barbados, West Indies

f Department of Epidemiology and Public Health, Yale University, New Haven, Conn

g Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md

o Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md

h Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Md

i Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif

j Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa

k Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass

l University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany

m Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Mich

n National Heart and Lung Institute, Imperial College, London, United Kingdom

o Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Baltimore, Md

Reprint requests: Kathleen C. Barnes, PhD, the Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 3A.62, Baltimore, MD 21224.

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.

PII: S0091-6749(09)01316-5

doi:10.1016/j.jaci.2009.08.031

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