The etiology and reasons underlying the ethnic disparities in systemic sclerosis (SSc) remain unknown. African Americans are disproportionally affected by SSc and yet are underrepresented in research. The aim of this study was to comprehensively investigate the association of DNA methylation levels with SSc in dermal fibroblasts from patients of African ancestry. Reduced representation bisulfite sequencing (RRBS) was performed on primary dermal fibroblasts from 15 SSc patients and 15 controls of African ancestry, and over 3.8 million CpG sites were tested for differential methylation patterns between cases and controls. The dermal fibroblasts from African American patients exhibited widespread reduced DNA methylation. Differentially methylated CpG sites were most enriched in introns and intergenic regions while depleted in 5′ UTR, promoters, and CpG islands. Seventeen genes and eleven promoters showed significant differential methylation, mostly in non-coding RNA genes and pseudogenes. Gene set enrichment analysis (GSEA) and gene ontology (GO) analyses revealed an enrichment of pathways related to interferon signaling and mesenchymal differentiation. The hypomethylation of DLX5 and TMEM140 was accompanied by these genes’ overexpression in patients but underexpression for lncRNA MGC12916. These data show that differential methylation occurs in dermal fibroblasts from African American patients with SSc and identifies novel coding and non-coding genes.

中文翻译：

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非裔美国人患有系统性硬化症的皮肤成纤维细胞中的差异DNA甲基化景观

系统性硬化症（SSc）中种族差异的病因和原因仍未知。非裔美国人受到SSc的影响不成比例，但在研究中代表性不足。这项研究的目的是全面调查非洲裔患者皮肤成纤维细胞中DNA甲基化水平与SSc的关系。对来自15名SSc患者和15名非洲血统对照的原代皮肤成纤维细胞进行了代表性降低的亚硫酸氢盐测序（RRBS），并测试了380万个CpG位点的病例与对照之间的甲基化差异模式。来自非洲裔美国患者的真皮成纤维细胞显示出广泛的DNA甲基化降低。差异甲基化的CpG位点在内含子和基因间区域最富集，而在5'UTR，启动子，和CpG岛屿。十七个基因和十一个启动子显示出明显的甲基化差异，主要是在非编码RNA基因和假基因中。基因集富集分析（GSEA）和基因本体论（GO）分析揭示了与干扰素信号传导和间充质分化有关的途径的丰富。的低甲基化DLX5和TMEM140伴随着这些基因在患者中的过表达，但lncRNA MGC1291 6的过表达。这些数据表明，来自患有SSc的非洲裔美国患者的真皮成纤维细胞中发生了甲基化差异，并鉴定了新的编码和非编码基因。