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  • Review Article
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The role of genetics and epigenetics in the pathogenesis of systemic sclerosis

Key Points

  • Systemic sclerosis (SSc) is a complex autoimmune disease, the pathogenesis of which is influenced by genetic, epigenetic and environmental factors

  • Candidate-gene studies and genome-wide association studies have identified a large number of genetic susceptibility factors for SSc and its clinical phenotypes

  • The low concordance rate for monozygotic twins demonstrates that a genetic basis cannot account exclusively for SSc pathogenesis and that epigenetic factors influenced by the environment are important

  • Several DNA methylation patterns, histone modifications and microRNAs (miRNAs) are altered in different cell types from patients with SSc; altered circulating miRNAs are potentially useful as disease diagnostic and prognostic biomarkers

Abstract

Systemic sclerosis (SSc) is a complex autoimmune disease of unclear aetiology. A multitude of genetic studies, ranging from candidate-gene studies to genome-wide association studies, have identified a large number of genetic susceptibility factors for SSc and its clinical phenotypes, but the contribution of these factors to disease susceptibility is only modest. However, in an endeavour to explore how the environment might affect genetic susceptibility, epigenetic research into SSc is rapidly expanding. Orchestrated by environmental factors, epigenetic modifications can drive genetically predisposed individuals to develop autoimmunity, and are thought to represent the crossroads between the environment and genetics in SSc. Therefore, in addition to providing a comprehensive description of the current understanding of genetic susceptibility underlying SSc, this Review describes the involvement of epigenetic phenomena, including DNA methylation patterns, histone modifications and microRNAs, in SSc.

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Figure 1: The pathogenesis of SSc is influenced by genetic, epigenetic and environmental factors.48,101
Figure 2: SSc pathophysiology involves the dysregulation of multiple cell types.

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Acknowledgements

J.C.A.B. is sponsored by the VENI Laureate from the Dutch Association of Research (NWO) and M.R. is funded by a Marie Curie Intra-European Fellowship.

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J.C.A.B. and M.R. researched data for the article. All authors provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Timothy R. D. J. Radstake.

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Supplementary Table 1

Loci associated with SSc and its clinical phenotypes in candidate-gene studies and genome-wide association studies (DOCX 30 kb)

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Broen, J., Radstake, T. & Rossato, M. The role of genetics and epigenetics in the pathogenesis of systemic sclerosis. Nat Rev Rheumatol 10, 671–681 (2014). https://doi.org/10.1038/nrrheum.2014.128

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