Unfolding the pathogenesis of scleroderma through genomics and epigenomics

Abstract

With unknown etiology, scleroderma (SSc) is a multifaceted disease that comprises of immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated miRNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that were affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomincs and epigenomics research in SSc.

Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis

“…WNT5A, and Wnt signaling more generally, have been implicated in many processes known to be involved in SSc pathogenesis (Tsou and Sawalha 2017;Wei et al 2011;Katsumoto et al 2011;Lafyatis 2012), such as angiogenesis (Huang et al 2005), keratinocyte differentiation and inflammation signaling , and fibroblast proliferation (Vuga et al 2009). WNT5A has also been linked to cellular transdifferentiation, a family of processes by which differentiated cell types dedifferentiate and redifferentiate into another cell type.…”

Pathogen infections and primary biliary cholangitis

“…As in many other autoimmune diseases , genetic predisposing factors have been shown to be associated with disease progression in PBC. For example, epidemiological data indicated an increased prevalence of patients with PBC among first‐degree relatives and siblings of an index patient, in what is known as familial clustering of PBC .…”

Epigenetics and Axial Spondyloarthritis - DNA is not Destiny

“…This indicates an 'epi' genetic component to the etiopathogenesis of these diseases. Studies in SLE, RA, Sjogren's syndrome, scleroderma and recently vasculitis have suggested and confirmed this fact [3][4][5][6]. However, we are still in need of studies on Ax SpA where the strong association with a gene (HLA B27) was revealed almost 3 decades ago [7] and yet, the exact association between the HLAB27 gene and Ax SpA still remains unexplained.…”