Epigenome-wide association study of bronchodilator response in African Americans

Abstract

Introduction: African Americans are one of the populations with the highest asthma burden. Despite having lower bronchodilator response (BDR) than other ethnicities, albuterol is the most widely used drug for asthma treatment among them. BDR and other asthma-related traits are affected by genetics and environmental exposure. Despite DNA methylation (DNAm) capture both factors, its influence on BDR is unknown.

Aims and objectives: To identify DNAm changes associated with BDR.

Methods: African Americans with asthma from the SAGE study (n=221) with DNAm data profiled with the EPIC array (Illumina) were included in the discovery phase. The association between DNAm in whole-blood and BDR was assessed by linear regression models adjusting for age, sex, ancestry, and tissue heterogeneity. Genome-wide significant results (p<9x10^-8) were attempted for replication in Latinos from GALA II (n=189). The effect of genetic variation in DNAm was assessed by a methylation quantitative trait loci (meQTL) analysis using a false discovery rate (FDR) of 5%.

Results: Fifteen CpGs were significantly associated with BDR in African Americans (FDR<0.05) even in sensitivity analyses adjusting for socioeconomic factors, clinical parameters, and environmental exposures. The CpGs cg08241295 near FGL2 (p=6.8x10^-9) and cg15341340 at DNASE2 (p=7.8x10^-8) surpassed the genome-wide significance threshold. The CpG site at DNASE2 replicated with the same effect in Latinos (p=4.9x10^-3). In contrast, the effect of the CpG site near FGL2 was specific to African Americans and it was regulated by 100 meQTLs (FDR<0.05).

Conclusion: We revealed novel associations of population-specific and cosmopolitan epigenetic marks with BDR in pediatric asthma.