Please use this identifier to cite or link to this item: https://doi.org/10.1136/annrheumdis-2017-212454
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, D.J
Denton, C.P
Behmoaras, J
Petretto, E 
Keywords: gamma interferon antibody
lipopolysaccharide
GSDMA protein, human
transcriptome
tumor protein
Article
controlled study
disease association
down regulation
epigenetics
expression quantitative trait locus
gene expression regulation
genetic identification
genetic risk
genetic susceptibility
genetic transcription
genetic variability
genotype
glycolysis
human
hypoxia
immune response
macrophage
major clinical study
monocyte
mTOR signaling
priority journal
RNA sequence
systemic sclerosis
upregulation
adolescent
adult
case control study
child
cytology
female
genetic predisposition
genetics
genotyping technique
macrophage
male
metabolism
pathology
preschool child
quantitative trait locus
risk factor
signal transduction
skin
systemic sclerosis
young adult
Adolescent
Adult
Case-Control Studies
Child
Child, Preschool
Female
Genetic Predisposition to Disease
Genotyping Techniques
Humans
Macrophages
Male
Neoplasm Proteins
Quantitative Trait Loci
Risk Factors
Scleroderma, Systemic
Signal Transduction
Skin
Transcriptome
Young Adult
Issue Date: 2018
Publisher: BMJ Publishing Group
Citation: Moreno-Moral, A, Bagnati, M, Koturan, S, Ko, J.-H, Fonseca, C, Harmston, N, Game, L, Martin, J, Ong, V, Abraham, D.J, Denton, C.P, Behmoaras, J, Petretto, E (2018). Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk. Annals of the Rheumatic Diseases 77 (4) : 596-601. ScholarBank@NUS Repository. https://doi.org/10.1136/annrheumdis-2017-212454
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 (IFN?)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFN? 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. © 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.
Source Title: Annals of the Rheumatic Diseases
URI: https://scholarbank.nus.edu.sg/handle/10635/175120
ISSN: 0003-4967
DOI: 10.1136/annrheumdis-2017-212454
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