RT Journal Article SR Electronic T1 Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk JF Annals of the Rheumatic Diseases JO Ann Rheum Dis FD BMJ Publishing Group Ltd and European League Against Rheumatism SP annrheumdis-2017-212454 DO 10.1136/annrheumdis-2017-212454 A1 Aida Moreno-Moral A1 Marta Bagnati A1 Surya Koturan A1 Jeong-Hun Ko A1 Carmen Fonseca A1 Nathan Harmston A1 Laurence Game A1 Javier Martin A1 Voon Ong A1 David J Abraham A1 Christopher P Denton A1 Jacques Behmoaras A1 Enrico Petretto YR 2018 UL http://ard.bmj.com/content/early/2018/01/13/annrheumdis-2017-212454.abstract AB 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.