Linking genetic variation with epigenetic profiles in Sjögren's syndrome

Abstract

DNA methylation represents an important regulatory event governing gene expression that is dysregulated in Sjögren's syndrome (SjS) and a number of autoimmune/inflammatory diseases. As disease-associated single-nucleotide polymorphisms (SNPs) have relevance in controlling DNA methylation, 94 non-HLA SjS-SNPs were investigated, among them 57 (60.6%) with widespread effects on 197 individual DNA methylation quantitative trait loci (meQTL) were selected. Typically, these SNPs are intronic, possess an active promoter histone mark, and control cis-meQTLs located around transcription start sites. Interplay is independent of the physical distance between SNPs and meQTLs. Using epigenome-wide association study datasets, SjS-meQTLs were characterized (41 genes and 13 DNA methylation CpG motifs) and for the most part map to a pro-inflammatory cytokine pathway, which is important for the control of DNA methylation in autoimmune diseases. In conclusion, exploring meQTLs represents a valuable tool to predict and investigate downstream effects of genetic factors in complex diseases such as SjS.