Abstract
BackgroundSystemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology. Defining its etiology is important to allow the development of effective predictive, preventative, and therapeutic strategies. We conducted this epigenomic study to investigate the contributions of DNA methylation to the etiology of SSc while minimizing confounding due to genetic heterogeneity.MethodsGenomic methylation in whole blood from 27 twin pairs discordant for SSc was assayed over 450 K CpG sites. In silico integration with reported differentially methylated cytosines, differentially expressed genes, and regulatory annotation was conducted to validate and interpret the results.ResultsA total of 153 unique cytosines in limited cutaneous SSc (lcSSc) and 266 distinct sites in diffuse cutaneous SSc (dcSSc) showed suggestive differential methylation levels in affected twins. Integration with available data revealed 76 CpGs that were also differentially methylated in blood cells from lupus patients, suggesting their role as potential epigenetic blood biomarkers of autoimmunity. It also revealed 27 genes with concomitant differential expression in blood from SSc patients, including IFI44L and RSAD2. Regulatory annotation revealed that dcSSc-associated CpGs (but not lcSSc) are enriched at Encyclopedia of DNA Elements-, Roadmap-, and BLUEPRINT-derived regulatory regions, supporting their potential role in disease presentation. Notably, the predominant enrichment of regulatory regions in monocytes and macrophages is consistent with the role of these cells in fibrosis, suggesting that the observed cellular dysregulation might be, at least partly, due to altered epigenetic mechanisms of these cells in dcSSc.ConclusionsThese data implicate epigenetic changes in the pathogenesis of SSc and suggest functional mechanisms in SSc etiology.
Highlights
Systemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology
There is compelling evidence that DNA methylation plays a role in the pathogenesis of autoimmune diseases, and multiple epigenome-wide association studies revealed the existence of differentially methylated regions associated with, for example, systemic lupus erythematosus (SLE) [12,13,14,15,16,17], rheumatoid arthritis [18,19,20,21,22,23,24,25,26], or psoriasis [27,28,29,30,31,32]
We identified multiple DNA methylation loci associated with SSc, including sites with concomitant evidence of altered methylation in blood cells of lupus patients and genes with concomitant evidence of differential expression in blood cells from SSc patients
Summary
Systemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology. Defining its etiology is important to allow the development of effective predictive, preventative, and therapeutic strategies We conducted this epigenomic study to investigate the contributions of DNA methylation to the etiology of SSc while minimizing confounding due to genetic heterogeneity. There is compelling evidence that DNA methylation plays a role in the pathogenesis of autoimmune diseases, and multiple epigenome-wide association studies revealed the existence of differentially methylated regions associated with, for example, systemic lupus erythematosus (SLE) [12,13,14,15,16,17], rheumatoid arthritis [18,19,20,21,22,23,24,25,26], or psoriasis [27,28,29,30,31,32]. Disease-discordant monozygotic twins offer the ideal study design to investigate the association of DNA methylation with a disease, as it minimizes confounding due to genetic heterogeneity, sex-, age- and early-life environmental effects [35, 36]
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