Targeted epigenome sequencing of eosinophils reveals CpG sites and regulatory variants associated with asthma

Eosinophils are pro-inflammatory cells that play a central role in asthmatic inflammation. However, few studies have examined their methylation profiles in asthma, all relying on microarray-based approaches. Here, an epigenome-wide association study in 183 purified eosinophil samples from the Saguenay–Lac-Saint-Jean asthma family cohort was performed using a custom sequencing panel targeting 4,609,564 CpGs in immune regulatory regions. Two CpG sites in MAEA and SLC9A genes, known to be involved in immune function, were significantly associated with asthma, while five additional sites showed suggestive associations. Integration with genotype data (7,829,429 variants) and expression counts (17,513 genes) identified significant quantitative trait loci-mediated regulatory effects. Two CpG sites at Chr1:6,267,177, which is a suggestive association, and Chr2:103,279,574 were linked to expression of EFNA5 , GNAQ , and LIMK1, implicating them in eosinophil-driven asthma pathogenesis. This finding offers insights into the asthma’s epigenetic architecture, highlighting disease-relevant loci detectable through targeted analysis of eosinophils. • Analysis of eosinophil methylome in asthmatics identified 7 methylation sites. • Integration with genomics and transcriptomics linked 3 sites to 7 genes of interest. • EFNA5 , GNAQ and LIMK1 share pathways linked to asthma pathophysiology. • Eosinophil methylome study can address part of missing heritability in asthma.