Academic Journal
Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk
| العنوان: | Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk |
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| المؤلفون: | Moreno-Moral, Aida, Bagnati, M., Koturan, S., Ko, J.H., Fonseca, C., Harmston, N., Game, Laurence, Martín, J., Ong, V., Abraham, D. J., Denton, C.P., Behmoaras, J., Petretto, E. |
| المساهمون: | Medical Research Council (UK), Duke-NUS Medical School, Arthritis Research UK, NHS Foundation Trust |
| بيانات النشر: | BMJ Publishing Group |
| سنة النشر: | 2018 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | GSDMA, eQTL analysis, macrophage, systemic sclerosis |
| الوصف: | 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 (IFNα)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNα 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. ; Fundingthis work was supported by the Medical research Council (Mr/M004716/1 to JB and Ep, and Mr/n01121x/1 to JB), by the nMrC (grant CBrG15may062) and duke-nUS Medical School (to Ep), by the Arthritis research UK (19427), Scleroderma & raynaud’s UK and the royal ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 1468-2060 |
| Relation: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-66761-p; Publisher's version; http://dx.doi.org/10.1136/annrheumdis-2017-212454; Sí; Annals of the Rheumatic Diseases 77: 596- 601 (2018); http://hdl.handle.net/10261/229892; http://dx.doi.org/10.13039/501100000265; http://dx.doi.org/10.13039/501100000341 |
| DOI: | 10.1136/annrheumdis-2017-212454 |
| DOI: | 10.13039/501100000265 |
| DOI: | 10.13039/501100000341 |
| الاتاحة: | http://hdl.handle.net/10261/229892 https://doi.org/10.1136/annrheumdis-2017-212454 https://doi.org/10.13039/501100000265 https://doi.org/10.13039/501100000341 |
| Rights: | open |
| رقم الانضمام: | edsbas.A8A78AE2 |
| قاعدة البيانات: | BASE |
| تدمد: | 14682060 |
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| DOI: | 10.1136/annrheumdis-2017-212454 |