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Epigenome-Wide Association Study of Asthma Exacerbations in Europeans
Elena Martin-Gonzalez1, Javier Perez-Garcia1, Esther Herrera-Luis2
1Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain.
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.
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