Genetics and epigenetics in primary Sjögren's syndrome

Abstract

Primary Sjögren's syndrome (pSS) is considered to be a multifactorial disease, where underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to disease development. In the last 5 years, the first genome-wide association studies in pSS have been completed. The strongest signal of association lies within the HLA genes, whereas the non-HLA genes IRF5 and STAT4 show consistent associations in multiple ethnicities but with a smaller effect size. The majority of the genetic risk variants are found at intergenic regions and their functional impact has in most cases not been elucidated. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs play a role in the pathogenesis of pSS by their modulating effects on gene expression and may constitute a dynamic link between the genome and phenotypic manifestations. This article reviews the hitherto published genetic studies and our current understanding of epigenetic mechanisms in pSS.

Keywords: DNA methylation; GWAS; HLA; IRF5; STAT4; epigenetics; genetics; histone modification; non-coding RNA; primary Sjögren’s syndrome.

Fig. 1

Schematic representation of fundamental epigenetic mechanisms involved in the regulation of gene expression Histone modifications are covalent post-translational modifications within the N-terminal tail of histone proteins. The most studied histone marks include Ac, Me and P of lysine residues at histones H3 and H4. DNA methylation refers to the covalent modification of C residues to 5mC by DNMTs typically in the context of CpG dinucleotides. Histone modifications and DNA methylation modulate chromatin structure and transcriptional accessibility of the DNA, thereby altering gene expression. At the post-transcriptional level, miRNAs, a class of small ncRNA, can bind to mRNA of target genes interfering with their expression. 5mC: 5-methyl-cytosine; Ac: acetylation; C: cytosine; DNMTs: DNA methyltransferases; Me: methylation; P: phosphorylation.

Fig. 2

Illustration of genetic regulation of DNA methylation at the IRF5-TNPO3 pSS susceptibility locus Data presented here are derived from meQTL analysis by Imgenberg-Kreuz et al. [73]. Top panel: Results (as –log10 P-values) of the pSS case–control EWAS of 100 pSS patients and 400 controls, with cg04864179 being the top differentially methylated CpG site within this locus. Middle panel: Significant meQTLs analysed in 382 controls, genotyped on the ImmunoChip, with the lines connecting the CpG site and corresponding SNPs in darker grey representing a stronger significance of the meQTL. GWAS index SNPs are indicated in red. Bottom panel: The RefSeq genes in the region. meQTL: methylation quantitative trait loci.

Fig. 3

Schematic summary of genetic and epigenetic mechanisms associated with pSS susceptibility Boxes with pink borders represent genes with SNPs associated with pSS susceptibility at genome-wide significance outside of the HLA region and include BLK, CXCR5, GTF2I, IL12A, IRF5, OAS1, STAT4, TNFAIP3 and TNIP1. Green boxes: IFN-induced genes such as MX1, IFI44L, OAS1, OAS2, TNFSF13B and IRF7, with hypomethylated CpG sites in pSS. Orange boxes: meQTLs, referring to association between a genetic variant (SNP) and the methylation level at a nearby CpG site demonstrated at BLK, CXCR5, IL12A, IRF5-TNPO3, STAT4 and TNIP1. Blue boxes: Alterations in miRNA expression, including miRNA-146a, have been identified in pSS. meQTL: methylation quantitative trait loci.