A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

Abstract

Short-acting β ₂-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S ^{1, 2} . However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma ³ . To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69×10 ⁻⁹). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5×10 ⁻⁸). Our results failed to replicate in three additional populations of 416 Latinos and 1,615 African Americans. Our findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.