Genetics of Systemic Sclerosis


Systemic sclerosis is a connective tissue disease characterised by progressive vascular damage, autoimmune dysfunction and excessive collagen deposition leading to organ fibrosis. The pathogenesis of the disease is complex and still not fully understood. However, environmental, genetic and epigenetic factors seem to contribute to the heterogeneity of the disease and to the different clinical phenotypes. In the last decades, several genetic investigations were conducted to identify susceptible or protective loci. These studies contributed to the identification of HLA and non‐HLA loci of susceptibility to systemic sclerosis and, interestingly, most of them seem to be shared with other autoimmune diseases. Moreover, the emerging evidences of the role of innate immunity have been supported by the demonstration of polymorphisms associated with innate pathway dysregulation.

Key Concepts

  • SSc is a multifactorial disorder where genetic, epigenetic and environmental factors contribute to the development of the different expression of the disease.
  • Several HLA‐ and non‐HLA‐related loci of susceptibility seem to be associated with the development of different clinical subphenotypes of SSc.
  • The identification of interferon pathway‐associated genes variants suggests the role of innate immunity in SSc.
  • SSc shared several genetic markers with other autoimmune disorders supporting the theory of a common genetic autoimmunity component.
  • Enhancements in genetic and epigenetic studies may improve the understanding of the biological meaning of polymorphisms associated with SSc.

Keywords: systemic sclerosis; genetic factors; genome‐wide association study; epigenetic; interferon signature

Figure 1. Pathophysiology of SSc and signalling pathways involved.
Figure 2. SSc is a multifactorial and heterogeneous disease where genetic/epigenetic and environmental factors contributed to the development of different clinical phenotypes.


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Further Reading

Bhattacharyya S and Varga J (2015) Emerging roles of innate immune signalling and toll‐like receptors in fibrosis and systemic sclerosis. Current Rheumatology Reports 17: 2.

Ciechomska M, van Laar JM and O'Reilly S (2014) Emerging role of epigenetics in systemic sclerosis pathogenesis. Genes and Immunity 15 (7): 433–439.

Mayes MD (2012) The genetics of scleroderma: looking into the postgenomic era. Current Opinion in Rheumatology 24 (6): 677–684.

Salazar G and Mayes MD (2015) Genetics, epigenetics and genomics of systemic sclerosis. Rheumatic Diseases Clinics of North America 41 (3): 345–366.

Wu M and Mohan C (2015) B‐cells in systemic sclerosis: emerging evidence from genetics to phenotypes. Current Opinion in Rheumatology 27 (6): 537–541.

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Murdaca, Giuseppe, Magnani, Ottavia, and Puppo, Francesco(Apr 2018) Genetics of Systemic Sclerosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024859]