A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma
Authors: Spear Melissa L. , Hu Donglei , Pino-Yanes Maria , Huntsman Scott , Sonnenberg Anton S. M. , Eng Celeste , Levin Albert M. , White Marquitta J. , McGarry Meghan E. , Thakur Neeta , Galanter Joshua M. , Mak Angel C. Y. , Oh Sam S. , Davis Adam , Kumar Rajesh , Farber Harold J. , Meade Kelly , Avila Pedro C. , Serebrisky Denise , Lenoir Michael A. , Brigino-Buenaventura Emerita A. , Rodriquez Cintron William , Thyne Shannon M. , Rodriguez-Santana Jose R. , Ford Jean G. , Chapela Rocio , Moreno Estrada Andrés , Sandoval Karla , Seibold Max A. , Williams L. Keoki , Winkler Cheryl A. , Hernandez Ryan D. , Torgerson Dara G. , Burchard Esteban G. 
Published: June 2017

Background

Short-acting B2-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.S1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3

Objective

To identify genetic variants that may contribute to differences in BDR in African Americans with asthma.

Methods

We performed a genome-wide association study 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 3 genotypes. We used linear regression models adjusting for age, sex, body mass index 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. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations.

Results

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 ofPRKG1that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5 × 10−8).

Conclusions

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.

Key messages

A GWAS for BDR in African American children with asthma identified an intergenic population specific variant at 9q21 to be associated with increased bronchodilator drug response (BDR).

A meta-analysis of GWAS across African Americans and Latinos identified shared genetic variants at 10q21 in the intron ofPRKG1to be associated with differences in BDR.

Further genetic studies need to be performed in diverse populations to identify the full set of genetic variants that contribute to BDR.