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  • Review Article
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New insights into the genetics and epigenetics of systemic sclerosis

Nature Reviews Rheumatology volume 14, pages 657–673 (2018)Cite this article

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Abstract

Systemic sclerosis (SSc) is a severe autoimmune disease that is characterized by vascular abnormalities, immunological alterations and fibrosis of the skin and internal organs. The results of genetic studies in patients with SSc have revealed statistically significant genetic associations with disease manifestations and progression. Nevertheless, genetic susceptibility to SSc is moderate, and the functional consequences of genetic associations remain only partially characterized. A current hypothesis is that, in genetically susceptible individuals, epigenetic modifications constitute the driving force for disease initiation. As epigenetic alterations can occur years before fibrosis appears, these changes could represent a potential link between inflammation and tissue fibrosis. Epigenetics is a fast-growing discipline, and a considerable number of important epigenetic studies in SSc have been published in the past few years that span histone post-translational modifications, DNA methylation, microRNAs and long non-coding RNAs. This Review describes the latest insights into genetic and epigenetic contributions to the pathogenesis of SSc and aims to provide an improved understanding of the molecular pathways that link inflammation and fibrosis. This knowledge will be of paramount importance for the development of medicines that are effective in treating or even reversing tissue fibrosis.

Key points

  • Systemic sclerosis (SSc) is a complex fibrotic, autoimmune disease, the manifestations of which are only partially explained by genetic predisposition.

  • The concordance rate for SSc in monozygotic twins is low, indicating that genetic predisposition is insufficient to explain disease development and suggesting a role for environmental factors and epigenetic influences.

  • Epigenetic factors associated with SSc include changes in DNA methylation, histone modifications and the expression of microRNAs and long non-coding RNAs, which together drive aberrant immune activation and fibrosis.

  • Integration of the knowledge derived from genomic and epigenomic studies in SSc is needed to improve the characterization of the disease.

  • Therapies that target epigenetic pathways are emerging as promising therapeutic tools in experimental models of fibrosis, raising hope for future applications in SSc.

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Fig. 1: Key epigenetic processes.
Fig. 2: Genetic and epigenetic influences on the pathogenesis of systemic sclerosis.

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Reviewer information

Nature Reviews Rheumatology thanks Y. Asano, M. Whitfield and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. These authors contributed equally: Chiara Angiolilli, Wioleta Marut.

Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

    Chiara Angiolilli, Wioleta Marut, Maarten van der Kroef, Eleni Chouri, Kris A. Reedquist & Timothy R. D. J. Radstake

  2. Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

    Chiara Angiolilli, Wioleta Marut, Maarten van der Kroef, Eleni Chouri, Kris A. Reedquist & Timothy R. D. J. Radstake

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Contributions

C.A., W.M., M.v.d.K. and E.C. researched data for the article. C.A., W.M., M.v.d.K., E.C. and T.R.D.J.R. wrote the article. C.A., W.M., K.A.R. and T.R.D.J.R. made substantial contributions to discussion of content. All authors reviewed and/or edited the manuscript before submission. M.v.d.K. and E.C. contributed equally to the preparation of this manuscript.

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Glossary

DNA methylation

An epigenetic change to DNA that conventionally creates a close, inactive chromatin state that results in transcriptional repression.

Histone post-translational modifications

Chemical modifications to histone tails (such as acetylation and methylation) that influence the accessibility of the DNA to the transcription machinery, thereby allowing or repressing gene expression.

Immunochip

Single nucleotide polymorphism microarrays designed to replicate and establish statistically significant genome-wide association study loci associated with autoimmune and inflammatory disorders.

MicroRNA

A short non-coding RNA of 18–24 nucleotides in length that regulates gene expression by binding to its complementary sequence within a target mRNA.

Long non-coding RNA

A long non-coding RNA ~200 nucleotides in length that functions as a molecular scaffold to regulate gene expression at the transcriptional, post-transcriptional and epigenetic levels.

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Angiolilli, C., Marut, W., van der Kroef, M. et al. New insights into the genetics and epigenetics of systemic sclerosis. Nat Rev Rheumatol 14, 657–673 (2018). https://doi.org/10.1038/s41584-018-0099-0

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