Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Abstract

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

Epigenetics: An opportunity to shape innate and adaptive immune responses

“…Recently, the evolutionarily conserved Wnt pathway, which regulates crucial aspects of cell fate determination during embryogenesis, has also been reported to increase skin fibrosis in SSc patients via epigenetic dysregulation; treatment with 5-azacitidine (5-Aza) abolishes the fibrotic phenotype [175][176][177]. Noteworthy, in peripheral blood cells of SS patients, the same hypomethylation of the type I IFN signalling pathwayassociated genes is coupled with hypermethylation of RUNX1 and Foxp3 genes, important in the control of Treg cell generation and function [178,179] (Table 1).…”

Multi-Omic Biomarkers for Patient Stratification in Sjogren’s Syndrome—A Review of the Literature

“…Although the aetiology of SS is unknown, it is considered that different factors, such as environmental, genetic and epigenetic, contribute to the disease pathogenesis. In this context, several studies [ 40 , 41 , 42 , 43 ], have focused on finding genetic and epigenetic factors that could be associated with SS. Transcriptomics, genome-wide association studies (GWAS) to identify genomic variants that are statistically associated with a risk of suffering the disease and epigenetic studies to determine whether gene expression is active or inactive based on DNA methylation are widely used nowadays.…”

Machine Learning for the Identification of a Common Signature for Anti–SSA/Ro 60 Antibody Expression Across Autoimmune Diseases

“…The first gene, ATP10A , encoded 1 of the 5 P4 ATPase that requires interaction with transmembrane protein 30A to exit from the endoplasmic reticulum to the plasma membrane. ATP10A was recently linked to autoimmunity, as one study demonstrated that methylation qualitative trait loci regulated the methylation of the ATP10A gene in blood samples from patients with primary SS ( 34 ). Since this enzyme mainly transports 2 aminophospholipids: phosphatidylserine and phosphatidylethanolamine, which may be the target of minor autoantibodies in antiphospholipid syndrome (APS) ( 35 ), it is reasonable to speculate that there is a link between the presence of antiphospholipid antibodies and the increase in ATP10A transcript.…”