Systemic sclerosis pathogenesis: contribution of recent advances in genetics

Abstract

Purpose of review To review susceptibility genes and how they could integrate in systemic sclerosis (SSc) pathophysiology providing insight and perspectives for innovative therapies. Recent findings SSc is a rare disease characterized by vasculopathy, dysregulated immunity and fibrosis. Genome-Wide association studies and ImmunoChip studies performed in recent years revealed associated genetic variants mainly localized in noncoding regions and mostly affecting the immune system of SSc patients. Gene variants were described in innate immunity (IRF5, IRF7 and TLR2), T and B cells activation (CD247, TNFAIP3, STAT4 and BLK) and NF-κB pathway (TNFAIP3 and TNIP1) confirming previous biological data. In addition to impacting immune response, CSK, DDX6, DNASE1L3 and GSDMA/B could also act in the vascular and fibrotic components of SSc. Summary Although genetic studies highlighted the dysregulated immune response in SSc, future research must focus on a deeper characterization of these variants with determination of their functional effects. Moreover, the role of these genes or others on specific vasculopathy and fibrosis would provide insight. Establishment of polygenic score or integrated genome approaches could identify new targets specific of SSc clinical features. This will allow physicians to propose new therapies to SSc patients.

Screening and identification of potential biomarkers and therapeutic targets for systemic sclerosis-associated interstitial lung disease

“…39 There was a close genetic linkage between A20 and SSc, as a number of cohort studies show that single nucleotide polymorphisms (SNPs) about A20 are closely related to the susceptibility of SSc, [41][42][43][44] and the genome-wide association studies and immunochip studies conducted in recent years have also confirmed that the gene variation of TNFAIP3 is related to SSc. 45 Another study observed the expression of A20 by culturing human skin fibroblasts in vitro. 46 This study also observed the effect of A20 overexpression or small interfering RNA (siRNA)-mediated A20 knockdown in human skin fibroblasts on the fibrotic responses induced by TGF-b.…”

The Versatile Gasdermin Family: Their Function and Roles in Diseases

“…Several studies have implicated GSDMs in autoimmune and inflammation-driven diseases. GSDMA mutants have been linked to limited cutaneous system sclerosis ( 33 , 34 ) and inflammatory bowel disease ( Table 1 ) ( 35 ). The results of transethnic meta-analysis of genome-wide associated studies involving Japanese and European populations with a total of 4,436 cases and 14,751 controls revealed that a missense mutation in GSDMA (rs3894194) is associated with system sclerosis.…”

Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension

“…Many studies have some evidence supporting the critical role of these signaling pathways and immune dysregulation in the pathogenesis of SSc ( 45 ). One study showed that stimulation of dendritic cells carrying this variant of SSc with a TLR2 agonist increased macrophage activation, resulting in increased production of interleukin-6 (IL-6) and tumor necrosis factor ( 46 ), thus participating in the pathogenesis of SSc.…”