Abstract
ObjectivesSeveral 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Systemic sclerosis (SSc) is an intractable chronic autoimmune disease of unknown aetiology with high clinical heterogeneity and mortality rates
Candidate gene and genetic screen studies have begun to elucidate the genetic architecture of SSc3; for instance, genome-wide association studies (GWAS) and whole exome sequencing (WES)[4] have reported numerous genes associated with susceptibility to SSc or to SSc subphenotypes and related traits.[5]
We revealed hundreds of genes associated with SSc in monocytederived macrophages (MDMs), including genes previously implicated in the genetic aetiology of the disease
Summary
Systemic sclerosis (SSc) is an intractable chronic autoimmune disease of unknown aetiology with high clinical heterogeneity and mortality rates. SSc is characterised by complex inflammatory, vascular and fibrogenic interactions occurring in multiple systems and tissues.[1] Among the cellular populations contributing to the pathogenesis of SSc, monocytes/macrophages have been suggested to play a key role in initiating and/or perpetuating the disease,[2] but their specific role and importance are still unclear. Gene sets representative of macrophage activation have been used for enrichment analyses in expression profiles obtained from SSc-associated tissues,[6] but the direct link between SSc disease variants and macrophage transcriptome remains to be elucidated
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