Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk

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Title: Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk
Authors: Moreno-Moral, A
Bagnati, M
Koturan, S
Ko, J-H
Fonseca, C
Harmston, N
Game, L
Martin, J
Ong, V
Abraham, DJ
Denton, CP
Behmoaras, J
Petretto, E
Item Type: Journal Article
Abstract: 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.
Issue Date: 17-Jan-2018
Date of Acceptance: 27-Dec-2017
ISSN: 0003-4967
Publisher: BMJ Publishing Group
Start Page: 596
End Page: 601
Journal / Book Title: Annals of the Rheumatic Diseases
Volume: 77
Copyright Statement: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: MR/M004716/1
Keywords: GSDMA
eQTL analysis
systemic sclerosis
1103 Clinical Sciences
1107 Immunology
1117 Public Health And Health Services
Arthritis & Rheumatology
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine

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