Background/Purpose Systemic sclerosis (SSc) is a chronic, multisystem, autoimmune inflammatory disease with genetic and non-genetic contributions to risk. The etiology of SSc, including the reasons underlying the wide variation in disease heterogeneity and severity remain unknown. The low concordance rate (4.2%) between monozygotic twins suggests an important role for acquired genetic changes such as epigenetic factors in SSc susceptibility. In order to characterize the genome-wide DNA methylation profile of blood and dermal fibroblasts in SSc, we performed an epigenome-wide analysis of DNA methylation on twin pairs discordant for SSc.

Methods DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip, which allows the annotation of approximately 480,000 CpG sites. Genome-wide methylation was assessed in genomic DNA isolated from: (1) blood from 34 discordant twin pairs, and (2) skin fibroblasts cultured from dermal punch biopsies of 12 twin pairs discordant for SSc. An efficiency analysis was performed with caGEDA to determine best normalization and feature selection methods and identify differentially methylated probes between unaffected and affected twins. Ingenuity Pathway Analysis (IPA) was used for pathway analysis.

Results We identified 68 CpGs in blood and 103 CpGs in dermal fibroblasts with significant changes in DNA methylation levels between the SSc-affected and healthy twins. These CpGs locate to 55 genes in the blood and 73 in the fibroblasts. While 45 (66%) CpGs were hypomethylated in the blood of the affected twin, 63 (58%) were hypomethylated in the dermal fibroblasts. Pathway analysis of the genes differentially methylated in the blood revealed an enrichment of genes in the antigen-presentation pathway (P=2.47E-06) and genes involved in dermatological, immunological and hematological diseases (P=1.98E-05). These enrichments were mostly driven by multiple probes in genes in the HLA region that consistently showed either hyper- or hypomethylation in the affected twins. In skin fibroblasts, pathway analysis revealed an enrichment of genes involved in gene expression (P=8.5E-06) and organismal development (P=1.90E-05). Prominent members of the differentially methylated genes included HOX and T-box transcription factor genes that showed multiple probes with consistent hyper- or hypomethylation in the affected twins.

Conclusion These data support a role for DNA methylation differences in mediating susceptibility to SSc and identify gene sets with differential methylation that may be involved in the pathogenesis of the disease. The distinct methylation profiles observed between blood and dermal fibroblasts suggest that tissue-specific epigenetic signatures may be responsible for the clinical heterogeneity of the disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-analysis-of-twin-pairs-discordant-for-systemic-sclerosis-reveals-distinct-signatures-in-blood-and-dermal-fibroblasts/