About this condition
Scleroderma — Genetic Susceptibility
Systemic sclerosis (scleroderma, SSc) is an autoimmune connective tissue disease characterized by vascular dysfunction, immune activation, and progressive fibrosis. It affects approximately 100,000 Americans. SSc has significant genetic heritability — first-degree relatives have 13-15x increased risk. HLA class II variants (DRB1*11:04, DPB1*13:01) are the strongest genetic associations, and different HLA alleles associate with specific autoantibody subtypes.
Non-HLA genetic associations include IRF5 (interferon regulatory factor 5 — also associated with lupus), STAT4, CD247, TNFSF4, and BANK1. These innate and adaptive immune pathway genes support the autoimmune pathogenesis model. Genetic variants in fibrosis pathways (CTGF, FBN1 microsatellite) may influence disease severity and organ involvement.
Clinical genetic utility: HLA genotyping can support SSc subtype classification (limited vs. diffuse), autoantibody prediction, and organ involvement risk stratification. Anti-RNA polymerase III autoantibodies (associated with specific HLA genotypes) require cancer screening (concurrent malignancy in ~10%). Nintedanib (anti-fibrotic) is FDA-approved for SSc-ILD, and tocilizumab for early diffuse SSc — treatment selection increasingly informed by molecular disease characterization.
Anti-RNA polymerase III scleroderma has ~10% concurrent cancer rate. Cancer screening is REQUIRED for this autoantibody subtype. HLA genotype predicts which autoantibody pattern — and therefore which cancer screening — applies.
- Gene locus
- HLA-DRB1 (6p21.32), IRF5 (7q32.1), STAT4 (2q32.2), CD247 (1q24.2), BANK1 (4q24)
