Objectives Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc. Methods We carried out RNA sequencing and genome-wide genotyping in MDMs from 57 patients with SSc and 15 controls. Our differential expression and expression quantitative trait locus (eQTL) analysis in SSc was further integrated with epigenetic, expression and eQTL data from skin, monocytes, neutrophils and lymphocytes. Results We identified 602 genes upregulated and downregulated in SSc macrophages that were significantly enriched for genes previously implicated in SSc susceptibility (P=5×10−4), and 270 cis-regulated genes in MDMs. Among these, GSDMA was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that GSDMA is upregulated in SSc MDMs (P=8.4×10−4) but not in the skin, and is a significant eQTL in SSc macrophages and lipopolysaccharide/interferon gamma (IFNγ)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNγ response pathways. Conclusions Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by GSDMA expression in macrophages.

中文翻译：

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巨噬细胞转录组的变化与系统性硬化症相关并介导 GSDMA 对疾病风险的贡献

目的 系统性硬化症 (SSc) 的几种常见和罕见的风险变异已被报道，但介导这些遗传变异功能的效应细胞仍有待阐明。虽然先天免疫细胞已被提议作为干扰 SSc 疾病过程的关键目标，但没有研究全面确定它们的效应作用。在这里，我们研究了单核细胞衍生的巨噬细胞 (MDM) 在介导 SSc 遗传易感性中的贡献。方法 我们对来自 57 名 SSc 患者和 15 名对照的 MDM 进行了 RNA 测序和全基因组基因分型。我们在 SSc 中的差异表达和表达数量性状基因座 (eQTL) 分析进一步与来自皮肤、单核细胞、中性粒细胞和淋巴细胞的表观遗传、表达和 eQTL 数据相结合。结果我们在 SSc 巨噬细胞中鉴定了 602 个上调和下调的基因，这些基因显着富集了先前与 SSc 易感性有关的基因（P=5×10-4），以及 MDM 中的 270 个顺式调节基因。其中，据报道 GSDMA 携带 SSc 风险变体 (rs3894194)，调节血液中邻近基因的表达。我们表明 GSDMA 在 SSc MDMs (P=8.4×10−4) 中上调，但在皮肤中没有，并且是 SSc 巨噬细胞和脂多糖/干扰素γ (IFNγ) 刺激的单核细胞中的重要 eQTL。此外，我们确定了 SSc 巨噬细胞转录组特征，其特征是糖酵解、缺氧和 mTOR 信号的上调以及 IFNγ 反应途径的下调。结论 我们的数据进一步确定了巨噬细胞和 SSc 之间的联系，