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Changes in macrophage transcriptome associate with systemic sclerosis and mediate contribution to disease risk. | LitMetric

AI Article Synopsis

  • The study investigates how monocyte-derived macrophages (MDMs) contribute to genetic risk factors associated with systemic sclerosis (SSc), focusing on the effects of specific genetic variants.
  • Using RNA sequencing and genome-wide genotyping on MDMs from SSc patients and controls, researchers identified 602 genes whose expression was altered in macrophages from SSc patients, indicating a link to disease susceptibility.
  • The findings suggest that the genetic variant rs3894194 influences SSc risk by affecting gene expression in macrophages, establishing a crucial role for these immune cells in the disease's pathology.

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), and 270 -regulated genes in MDMs. Among these, was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that is upregulated in SSc MDMs (P=8.4×10) 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 expression in macrophages.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890626PMC
http://dx.doi.org/10.1136/annrheumdis-2017-212454DOI Listing

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