rs2280714

This review article by Ota and Kuwana synthesizes genetic studies on systemic sclerosis (SSc), a complex autoimmune disease. Multiple genetic association studies, including GWAS and candidate gene approaches, have identified SSc susceptibility genes primarily involved in innate immunity (IRF4, IRF5, IRF7, IRF8, TNFAIP3), adaptive immune response (TNFSF4, CD247, PTPN22, CSK, STAT4, BLK), IL-12 signaling (IL-12A, IL-12RB1, IL-12RB2, TYK2), apoptosis/autophagy (ATG5, GSDMA, GSDMB, NOTCH4), and vascular homeostasis/fibrosis (PPARG). The review emphasizes that identified risk variants are predominantly located in non-coding regulatory regions and influence gene expression rather than protein structure.

This study of 492 SLE patients across three ancestry groups identified genetic variation at the IRF7/PHRF1 locus associated with autoantibody profiles and serum interferonα activity. The rs702966 C allele was associated with anti-dsDNA antibodies (OR=1.83, P=0.0069) in European and Hispanic Americans and with higher IFNα levels in anti-dsDNA-positive patients (P=4.1×10⁻⁵). The rs4963128 T allele was associated with anti-Sm antibodies (OR=1.95, P=0.0017) in African Americans and with increased IFNα levels in anti-Sm-positive African American patients (P=0.0012). These findings demonstrate autoantibody-dependent genetic effects on IFNα production through the endosomal TLR/IRF7 pathway in SLE pathogenesis.

This is a comprehensive review of genetic factors in systemic sclerosis (SSc), a complex autoimmune disease. The review synthesizes findings from candidate gene analysis and genome-wide association studies identifying numerous SNPs and genetic variants associated with SSc susceptibility, primarily in genes involved in innate immunity (IRF4, IRF5, IRF7, IRF8, TNFAIP3), adaptive immunity (TNFSF4, PTPN22, STAT4, BLK, PRDM1), and cell death pathways (ATG5, DNASE1L3, GSDMA/B, NOTCH4). HLA class II genes are associated with SSc-related autoantibodies rather than SSc itself, with DRB1 alleles carrying the FLEDR amino acid sequence critical for anti-topo I antibody responses.

This review updates knowledge on genetic factors in systemic sclerosis (SSc) susceptibility and disease expression. GWAS and candidate gene studies have identified multiple SSc-associated genetic variants primarily located in non-coding regions that influence gene expression through eQTL effects. Major risk genes include those involved in innate immunity (IRF4, IRF5, IRF7, IRF8, TNFAIP3), adaptive immune response (PTPN22, STAT4, TNFSF4, CD247), and cell death pathways (ATG5), while few genes directly involve fibrosis or vascular homeostasis. HLA class II genes associate with SSc-related autoantibodies rather than SSc itself. Multi-omics approaches are needed to characterize the complex molecular architecture and identify biomarkers.

A case-control study of 263 non-anterior uveitis patients and 724 healthy Spanish controls examined three IRF5 SNPs (rs2004640, rs2070197, rs10954213) for association with uveitis and macular edema. Two functional variants, rs2004640 and rs10954213, showed significant protective associations with absence of macular edema (OR=1.48, P_FDR=5.07E-03 and OR=1.54, P_FDR=3.37E-03, respectively), suggesting IRF5 genetic variation influences macular edema development in uveitis patients.

A case-control association study of 281 Japanese systemic sclerosis (SSc) patients and 477 healthy controls examined three IRF5 SNPs (rs2004640, rs10954213, rs2280714) previously associated with systemic lupus erythematosus. rs2280714 showed the strongest association with SSc (OR 1.42, P=0.0012 in all SSc; OR 1.70, P=0.00013 in diffuse cutaneous SSc). The rs2004640 association was replicated in the recessive model, particularly in the anti-topoisomerase I antibody-positive subset.

This study examined IRF5 genetic variants in 199 systemic lupus erythematosus (SLE) patients to determine if the IRF5 SLE risk haplotype associates with elevated serum interferon-α (IFN-α) activity. SLE patients with risk/risk or risk/neutral IRF5 genotypes showed significantly higher serum IFN-α activity compared to protective genotypes (P = 0.025), with the most pronounced effect in patients positive for anti-RBP or anti-dsDNA autoantibodies (P = 0.012). The rs3807306 genotype independently associated with high IFN-α levels in the autoantibody-positive subgroup.