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

Abstract

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 To test the hypothesis that some genes may contribute to the profound disparities in asthma. Methods We performed a genome-wide association study in two independent populations of African ancestry (935 African American asthma cases and controls from the Baltimore-Washington, D.C. area, and 929 African Caribbean asthmatics and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. Results Meta-analysis combining these two African-ancestry populations yielded three SNPs with a combined P-value <10-5 in genes of potential biological relevance to asthma and allergic disease: rs10515807, mapping to alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57×10-6); rs6052761, mapping to prion-related protein (PRNP) on chromosome 20pter-p12 (2.27×10-6); and rs1435879, mapping to dipeptidyl peptidase 10 (DPP10) on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of UK and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Conclusions Evidence for association was also examined in four additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. 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.

Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia

“…6 Seven GWAS of asthma have been published recently. [7][8][9][10][11][12][13] From these, three loci have emerged with reproducible effects on asthma risk in independent samples: the GSDMB/ORMDL3 locus (henceforth referred to as ORMDL3) on chromosome 17q12-21; 7 the PDE4D gene on chromosome 5q12 9 and the DENND1B on chromosome 1q31. 11 Three GWAS of asthma biomarkers were also published recently.…”

Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma

“…GRAAD (Genomic Research on Asthma in the African Diaspora) comprises NIH-funded studies of asthma in pediatric and adult African American populations and one study of healthy African Americans. 19 A diagnosis of asthma was based on both a reported history of asthma and a documented history of physician-diagnosed asthma. For each of the asthma studies, a standardized questionnaire based on either the American Thoracic Society 20 or The International Study of Asthma & Allergy in Childhood (ISAAC) standards was administrated by a clinical coordinator.…”

“…Seven SNPs included in Illumina HumanHap650Y version 1 and 3 BeadChips (rs5409541, rs10518263, rs39711, rs10408249, rs36496, rs36498, rs11672925) were genotyped using the Illumina's BeadArray at the Center for Inherited Disease Research (CIDR) as described previously. 19 The rest of the SNPs were genotyped using customdesigned primers and probes for the TaqMan Allelic Discrimination assays using the 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA). 26 Six SNPs, including four SNPs in the regulatory regions (rs6509541, rs39711, rs10420357, rs36498) and two (rs3829659 Arg388Gly and rs10409962 Ser170-Pro) in the coding regions of the Siglec-8 gene, were genotyped among 356 nuclear Brazilian families using TaqMan assays.…”

“…Quality control for genotyping was described previously. 19,28 Briefly, quality-control measures included a genotyping call rate of 495%, with no discordances on repeat genotyping of Siglec-8 variations and asthma P-S Gao et al a random 5% of the sample, no significant departures from Hardy-Weinberg Equilibrium within each study group (exact P-value40.01), MAF 45%, and Mendelian errors in 5% or more of the marker. Population admixture among African Americans was evaluated by genotyping 416 SNPs identified as ancestry-informative markers (AIMs) as described previously.…”

“…Population admixture among African Americans was evaluated by genotyping 416 SNPs identified as ancestry-informative markers (AIMs) as described previously. 19 …”