Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD

Disclosures

Lab Med. 2011;42(9):562-572. 

In This Article

Genetics

Systemic sclerosis is a complex disorder with strong aspects of genetic predisposition. The most prominent genetic factor is gender (female:male = 3:1 to 6:1). Another is the human major histocompatibility complex (MHC). In SSc, the prevalence in first-degree relatives is 1.6% and in monozygotic twins is 4.7% as compared to 0.026% in the general population.[19] The increased spontaneous and clastogen-induced chromosomal damage rates indicate that SSc lymphocytes may be susceptible to DNA damage caused by free radicals.[20]

In addition to associations between Auto-ab (ACA, ATA) and various HLA-alleles,[22] the more consistent susceptibility genes reflect the associations of single nucleotide polymorphisms (SNP) in genes involved in autoimmune regulation (including innate immunity, T cell differentiation, and immune-cell signaling), vascular function, and extracellular matrix (ECM) with SSc. They are partly shared with other autoimmune diseases. Systemic sclerosis has been linked to interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription 4 (Stat4), protein tyrosine phosphatase, non-receptor type 22 (PTPN22) and B cell scaffold protein with ankyrin repeats 1 (BANK1), connective tissue growth factor (CTGF), T-box transcription factor (TBX21), Corf13-BLK, interleukin 10 receptor (IL-10R), interleukin 23 receptor (IL-23R), and tumor necrosis factor superfamily (TNFSF4).[19,21] Polymorphisms in the fibrillin gene have been described in the Choctaw Indians in association with the ATA-positive diffuse SSc.[22] In the future, we need a better understanding of how these polymorphisms lead to the development of SSc and how the gene-gene as well as gene-environment interactions function.

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