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

Rasika A Mathias, Audrey V Grant, Nicholas Rafaels, Tracey Hand, Li Gao, Candelaria Vergara, Yuhjung J Tsai, Mao Yang, Monica Campbell, Cassandra Foster, Peisong Gao, A Togias, Nadia N Hansel, Gregory Diette, N Franklin Adkinson, Mark C Liu, Mezbah Faruque, Georgia M Dunston, Harold R Watson, Michael B Bracken, Josephine Hoh, Pissamai Maul, Trevor Maul, Anne E Jedlicka, Tanda Murray, Jacqueline B Hetmanski, Roxann Ashworth, Chrissie M Ongaco, Kurt N Hetrick, Kimberly F Doheny, Elizabeth W Pugh, Charles N Rotimi, Jean Ford, Celeste Eng, Esteban G Burchard, Patrick M A Sleiman, Hakon Hakonarson, Erick Forno, Benjamin A Raby, Scott T Weiss, Alan F Scott, Michael Kabesch, Liming Liang, Gonçalo Abecasis, Miriam F Moffatt, William O C Cookson, Ingo Ruczinski, Terri H Beaty, Kathleen C Barnes
Journal of Allergy and Clinical Immunology 2010, 125 (2): 336-346.e4

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 alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 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.

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