Systemic Sclerosis is a Complex Disease Associated Mainly with Immune Regulatory and Inflammatory Genes

Abstract

Systemic sclerosis (SSc) is a fibrotic and autoimmune disease characterized clinically by skin and internal organ fibrosis and vascular damage, and serologically by the presence of circulating autoantibodies. Although etiopathogenesis is not yet well understood, the results of numerous genetic association studies support genetic contributions as an important factor to SSc. In this paper, the major genes of SSc are reviewed. The most recent genome-wide association studies (GWAS) are taken into account along with robust candidate gene studies. The literature search was performed on genetic association studies of SSc in PubMed between January 2000 and March 2014 while eligible studies generally had over 600 total participants with replication. A few genetic association studies with related functional changes in SSc patients were also included. A total of forty seven genes or specific genetic regions were reported to be associated with SSc, although some are controversial. These genes include HLA genes, STAT4, CD247, TBX21, PTPN22, TNFSF4, IL23R, IL2RA, IL-21, SCHIP1/IL12A, CD226, BANK1, C8orf13-BLK, PLD4, TLR-2, NLRP1, ATG5, IRF5, IRF8, TNFAIP3, IRAK1, NFKB1, TNIP1, FAS, MIF, HGF, OPN, IL-6, CXCL8, CCR6, CTGF, ITGAM, CAV1, MECP2, SOX5, JAZF1, DNASEIL3, XRCC1, XRCC4, PXK, CSK, GRB10, NOTCH4, RHOB, KIAA0319, PSD3 and PSOR1C1. These genes encode proteins mainly involved in immune regulation and inflammation, and some of them function in transcription, kinase activity, DNA cleavage and repair. The discovery of various SSc-associated genes is important in understanding the genetics of SSc and potential pathogenesis that contribute to the development of this disease.

Genetics of systemic sclerosis

“…In the past year, two Immunochip [ 26 ▪ , 27 ▪ ], an Immunochip and GWAS follow-up [ 31 , 32 ], and a candidate gene study [ 73 ] reported novel strong and suggestive associations with SSc. The findings from these studies are discussed below, some of which have already been included in recent reviews [ 74 , 75 ]. The majority of these regions overlap with those implicated in other autoimmune diseases, underscoring the role of immune system dysregulation as a primary event in SSc pathogenesis.…”

“…Clearly, although fibroblast activation is the hallmark of SSc, most of the genetic factors associated with SSc lie in immune-related genes [ 71 , 75 ], and the reasons underlying the characteristic excess deposition of extracellular matrix (ECM) proteins remain elusive. The distinct genetic architecture of pulmonary fibrosis in SSc-associated interstitial lung disease compared with idiopathic pulmonary fibrosis is noteworthy, supporting a distinct genetic risk of these two forms of lung fibrosis and suggesting that fibrosis might be the result of different pathogenic mechanisms, with a more immune-driven cause in SSc [ 78 ].…”

Prediction of severity and subtype of fibrosing disease using model informed by inflammation and extracellular matrix gene index

“…More recently, investigators have focused on panels comprising a handful of biomarkers to predict disease severity based on gene expression profiling [ 2 , 5 ]. However, there have been no investigations that focused on the correlation between levels of chemokine and inflammation genes, which are known to be perturbed in disease [ 38 , 39 ], and the expression levels of ECM genes. Therefore, in the present study we sought to identify the inflammation and ECM genes that were most important in predicting patient severity or disease subset, using SSc as a prototype of fibrotic disease.…”

Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis–Associated Genetic and Environmental Factors

“…Genetic association studies have reported a number of SSc-associated genes including HLA genes (e.g. HLA-DQB1, -DPB1 and -DRB1 ), STAT4, IRF5, CD247, TBX21, BANK1, C8orf13, PTPN22, TNFSF4, FAS, TNFAIP3, CD226, IRAK1, MECP2, MIF, ITGAM, PLD4, TLR-2, CAV1, IL2RA, NLRP1, OPN, PXK, JAZF, KIAA0319, IL-6, IL-21, CXCL8, CSK, PSD3, NFKB1, XRCC1, XRCC4, CCR6, IRF8, GRB10, SOX5, NOTCH4, TNIP1, PSOR1C1, RHOB, DNASEIL3, SCHIP1/IL12A and ATG5 (1–27). On the other hand, studies of environmental hazards contributing to SSc were mainly suggested by occupations with high incidence of SSc.…”