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.
Highlights
Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands
We explored the DNA methylation patterns associated with SS comparing the whole blood DNA methylation level between 189 SS patients and 220 heathy subjects (Supplementary Table 1) using the Infinium MethylationEPIC BeadChip with which we could interrogate 776,284 autosomic CpG sites
The majority of SS-associated differential methylated positions (DMPs) exhibited decreased methylation levels in SS patients compared with controls (91.5%), supporting the overall hypomethylation previously described in SS patients (Fig. 1a)[19,20]
Summary
Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. 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. Epigenetic alterations can be integrators of the complex interaction between genes and the environment and are known to play a relevant role in autoimmunity by altering gene expression profiles in response to genetic factors, changing environment and immunological c onditions[17,18]. Gene expression profiling of minor salivary glands or peripheral blood showed a consistent upregulation of IFN-inducible genes associated with SS, which was found more pronounced in the subset of cases serologically defined by increased titers of anti-Ro/SSA and anti-La/SSB autoantibodies[22,23]
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