rs2304256

Case-control study in 642 Han Chinese SLE patients and 642 healthy controls examining polymorphisms in IRF5 and TYK2 genes. IRF5 rs2004640 (T allele, OR=1.41, p=0.0003) and protective haplotype DAG (OR=0.71, p=6.2×10⁻⁵) and risk haplotype IAT (OR=1.53, p=0.0005) showed significant association with SLE. TYK2 rs280500 (A allele, OR=1.47, p=8.83×10⁻⁶), rs2304256 (G allele, OR=1.59, p=3.71×10⁻⁶), and rs8108236 (A allele, OR=1.39, p=0.0004) were significantly associated with SLE. A three-way gene-gene interaction between TYK2 rs280500, rs2304256 and IRF5 rs10954213 was found (p<0.0001).

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 meta-analysis of 13 studies examined associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus (SLE) susceptibility. The rs6445975 polymorphism in PXK was significantly associated with increased SLE risk in Europeans (OR = 1.198, P = 3.4E-07) but not Asians. The rs2304256 polymorphism in TYK2 showed a protective association with SLE in Europeans (OR = 0.700, P = 1.3E-04) but not Asians. Other TYK2 variants (rs12720270, rs280519, rs12720356) showed no significant associations.

This pathway-based association study identified genetic variations in the IL7RA/IL7 signaling pathway that increase multiple sclerosis susceptibility. Two novel genes replicated in an independent dataset: IL7 (rs2587156, p=8.29×10−6, OR=1.35) and SOCS1 (rs441349, p=3.48×10−7, OR=1.25). Additional candidate genes with suggestive evidence include PRKCE (p=3.47×10−4), BCL2 (p=4.32×10−4), and TYK2. The study analyzed 2,961 MS cases and controls in discovery, with 4,831 samples in replication, examining 7,865 SNPs across 73 genes in this biologically-relevant immune pathway.

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.

This comprehensive review examines genetic associations in type I interferon-related signaling pathways across multiple autoimmune diseases. The authors review evidence linking dysregulated interferon alpha (IFNα) signaling to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other autoimmune conditions, identifying multiple susceptibility genes including IFIH1, IRF5, STAT4, TYK2, BLK, BANK1, FCGR2A, and TREX1 with well-replicated associations and functional relevance to IFN pathway dysfunction.