Genetic background of systemic sclerosis: autoimmune genes take centre stage

SSc is a complex multiorgan disease. The key steps in its pathogenesis include early endothelial damage, dysregulation of the immune system with abnormal autoantibody production and fibroblast activation resulting in hyperproduction of extracellular matrix. The disease is caused by an interaction between susceptibility genes and environmental triggers since epidemiological data, including family and twin studies, reveal a genetic component in the pathogenesis of SSc. The candidate gene approach has mainly been employed to identify SSc susceptibility genes. We will focus on data obtained through large samples of well-phenotyped patients and replicated in independent cohorts. These case-control association studies have enabled the identification of several genes that are shared with other connective tissue disorders, and for some of these, putative autoimmune susceptibility genes have been identified. Indeed, we will mainly focus on IRF5 (rs2004640), STAT4 (rs7574865), PTPN22 (rs2476601) and BANK1 (rs3733197 and rs10516487) data. Some of these genes/loci are common to several autoimmune diseases, indicating a shared genetic background also contributing to SSc. Among connective tissue disorders, similarities for genetic markers with SLE are noteworthy. Most likely, these immune-modifying genes could interact and influence both disease phenotype and severity. Less evidence is available yet with regard to genetic markers relating to the vascular and fibrotic aspects of the disease.