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 |
Appears in Collections: | Staff Publications Elements |
Show full item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1136_annrheumdis-2017-212454.pdf | 2.71 MB | Adobe PDF | OPEN | None | View/Download |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.