Epigenome-wide association study and functional analyses reveal regulatory loci linked to lung function and diabetes in cystic fibrosis

Abstract

While the genetic basis of cystic fibrosis is well-established, the genotype alone does not explain the substantial inter-individual variability in disease expression, particularly in pulmonary outcomes. Non-hereditary factors, such as epigenetic modifications, may contribute to this clinical heterogeneity. To investigate the clinical variability in cystic fibrosis, we profiled DNA methylation in 64 blood samples from the MethylCF cohort and conducted an epigenome-wide association study. DNA methylation levels were corrected for cell count heterogeneity. We analysed associations between DNA methylation levels and disease status, lung function, body mass index, and cystic fibrosis-related diabetes. Genes in the JAK/STAT pathway exhibited methylation changes and differential expression in patient blood samples. Differentially methylated regions were enriched for binding sites of interferon regulatory factor 1. Functional and in silico analyses of seven top-differentially methylated loci revealed regulatory roles for four regions associated with SOCS3 , RGS1 , ASPH , and LYN . Notably, methylation at cg02586212 ( RGS1 ) was associated with cystic fibrosis-related diabetes and genetically controlled by a methylation quantitative trait locus that explained 30% of DNA methylation variance in our cohort. Additionally, differentially methylated CpG sites at SOCS3 , SBNO2 , and RGS1 overlapped with those observed in chronic obstructive pulmonary disease and rheumatoid arthritis, suggesting shared systemic inflammatory mechanisms. Our findings highlight the biological relevance of epigenetic modifications in cystic fibrosis and support systemic inflammation as a common driver of differential DNA methylation across inflammatory diseases. The study is registered at clinical.gov under reference #NCT02884622.