Current understanding of the genetic model of systemic sclerosis

ABSTRACT. Systemic sclerosis (SSc) is a rare systemic autoimmune disease of connective tissue characterized by a markedly heterogeneous clinical course and multiorgan involvement. The etiology of the disease is considered the result of a complex interaction between exogenous trigger factors and a genetic predisposition. Viral and bacterial infections, occupational hazards (exposure to silica dust, chemicals), and exposure to cold are discussed in the current literature as potential triggers. Along with studying these external factors, in recent years, scientists have focused on identifying new genetic markers for the development of SSc. An analysis of current data on the genetic basis of predisposition to SSс and the mechanisms of its development was conducted based on a review of literature data for the period from 2010 to 2026. A search for relevant sources was conducted in the international databases PubMed, Scopus, Web of Science, as well as in the Russian scientific electronic library eLibrary.ru.

For citation: Trofimova AS, Chernyavskaya MA, Mazurov VI, Leineman IA, Trofimov EA. Current understanding of the genetic model of systemic sclerosis. Therapy (Moscow). 2026;12(5S):116–123.
https://doi.org/10.18565/ therapy.2026.5-s5.116-123

INTRODUCTION

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune activation, cutaneous and internal organ fibrosis, and widespread vasculopathy [1]. The reported prevalence of SSc varies widely across geographic and ethnic populations, ranging from 3.1 to 144.5 cases per 100,000. Like many autoimmune diseases, SSc predominantly affects women, with incidence peaking between 40 and 50 years of age [2].

The etiology of SSc remains incompletely understood; however, the disease is thought to develop when environmental triggers act in genetically susceptible individuals [3]. Major triggers include occupational exposure to chemicals such as silica, pesticides, organic solvents, and epoxy resins, as well as infectious agents. Although SSc is considered a sporadic disease, the literature also provides evidence of familial predisposition [4]. Familial cases account for approximately 1.6%, whereas the estimated risk in the general population is only 0.026%, indicating substantial familial aggregation. Quantitative risk estimates indicate a 15-fold increase among siblings and a 13-fold increase among first-degree relatives. Individuals of African ancestry are also known to be affected by SSc more frequently and to have an earlier age at disease onset and a more aggressive disease course than individuals of European ancestry.

Although the available epidemiological evidence strongly supports a familial predisposition to SSc, current research is increasingly focused on identifying specific genetic markers of the disease. However, the number of comprehensive studies in this area remains limited, primarily because of the polygenic nature of SSc. Its genetic landscape substantially overlaps with that of other autoimmune diseases, making it difficult to identify SSc-specific genetic determinants [5]. Nevertheless, two principal approaches – candidate gene studies and genome-wide association studies (GWAS) – have led to considerable progress in elucidating the complex genetic architecture of SSc and have identified a broad range of polymorphisms implicated in its pathogenesis. The evidence accumulated to date has revealed several genetic markers associated with the development of SSc complications; however, genetic predictors of susceptibility to the disease itself remain insufficiently characterized.

This review summarizes the major genetic factors associated with susceptibility to SSc and examines the potential associations between genetic markers and the principal clinical manifestations of the disease in light of current knowledge of the role of genetic alterations.

Genetic variation resulting from polymorphisms in two major groups of genes – the human leukocyte antigen (HLA) region and non-HLA genes – is considered to play a central role in the development of SSc [5]. The non-HLA group includes genes encoding interferon regulatory factors (IRFs); the signal transducer and activator of transcription 4 gene (STAT4) and the Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathway; Toll-like receptors (TLRs); components of the nuclear factor kappa B (NF-κB) signaling pathway; macrophage migration inhibitory factor (MIF); interleukin 1 receptor-associated kinases; the interleukin 12 (IL-12) axis and its receptors; and the TNF superfamily member 4 (TNFSF4) and interleukin 6 (IL6) genes [3].

GENES IN THE HLA REGION

The HLA region contains a high concentration of genes essential for immune responses and thus represents the most important genetic cluster encoding key regulators of immune function [6]. It is therefore unsurprising that robust associations between the HLA region and autoimmune diseases have been recognized for more than five decades.

Genome-wide association studies have confirmed that the HLA region is the strongest susceptibility locus for SSc [7]. Twelve loci within this region have been associated with susceptibility to the disease, including HLA-B, HLA-C, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DPB1, and HLA-DPB2. The strongest associations were reported for the HLA-DRB1*11:04, HLA-DQA1*05:01, HLA-DQB1*03:01, and HLA-DQB1 alleles.

Associations between HLA haplotypes and the two major cutaneous subsets of SSc – diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) – are largely driven by their relationships with SSc-specific autoantibodies [8, 9]. An analysis of HLA-DRB1 and HLA-DQB1 associations across autoantibody-defined subgroups found that HLA-DRB1*11 was the only allele consistently associated with anti-topoisomerase I antibody (ATA) positivity and with dcSSc. By contrast, HLA-DRB1*01, HLA-DRB1*04, HLA-DRB1*08, HLA-DQB1*05:01, and the HLA-DQB1 position 26 epitope were associated with anticentromere antibodies (ACA), which are characteristic of lcSSc.

A more detailed picture of HLA allele distribution across SSc subsets emerged from a recent study led by Spanish investigators [10]. Six i...

A.S. Trofimova, M.A. Chernyavskaya, V.I. Mazurov, I.A. Leineman, E.A. Trofimov