Epigenome‐Wide Association Study of Asthma Exacerbations in Europeans

ABSTRACT Background Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered. Objective This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans. Methods DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome‐wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome‐wide significance ( p < 9 × 10 −8 ) was declared after meta‐analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis‐methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted. Results Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta‐analysis (annotated to ZBTB16 and BAIAP2 ). Of those, CpG cg25345365 ( ZBTB16 ) was cross‐tissue validated in nasal epithelium ( p = 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune‐mediated diseases, and mortality. Conclusions DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.