rs2230926

Genome-wide association study in 1,174 Korean SLE cases and 4,248 controls identified 12 genome-wide significant loci, including a novel locus spanning ATG16L2, FCHSD2, and P2RY2 peaking at rs11235667 (P=1.0×10⁻⁸, OR=0.59). The study replicated 10 previously established SLE risk loci (STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, IRAK1-MECP2) and identified novel independent effects in TNFAIP3 and TNFSF4. HLA-DRB1*1501 and HLA-DQB1*0602 were the strongest HLA associations (P=5.55×10⁻¹⁶, OR=1.85 and OR=1.90 respectively).

This case-control study identified PLD4 as a novel susceptibility gene for systemic sclerosis (SSc) in a Japanese population, with rs2841277 showing significant association (P=0.00017, OR=1.25). The study also confirmed associations between SSc and rs6932056 in TNFAIP3 (P=0.0000095, OR=1.50) and rs2280381 in IRF8 (P=0.0030, OR=1.26). rs2841280 in PLD4 exon 2 was found in strong linkage disequilibrium with rs2841277 and introduces an amino acid change (E27Q).

Meta-analysis of 10 studies examining associations between TNFAIP3 polymorphisms (rs6920220, rs10499194, rs2230926) and rheumatoid arthritis across multiple ethnic populations. rs6920220 showed strong association with RA in Europeans (OR 1.227, p < 1.0×10⁻⁹), rs10499194 in Asians (OR 1.254, p = 6.7×10⁻⁴), and rs2230926 across all subjects (OR 1.390, p = 1.9×10⁻⁶).

This case-control study of 446 African-American RA patients and 733 controls identified three SNPs significantly associated with rheumatoid arthritis: TNFAIP3 rs719149 (A allele OR 1.22, p=0.02), TAGAP rs1738074 (G allele OR 0.75, p=0.0012), and TAGAP rs4709267 (G allele OR 0.74, p=0.004). Conditional analyses suggest the two TAGAP SNPs have independent effects despite weak linkage disequilibrium (R²=0.034).

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 association study of 664 German Wegener's granulomatosis (WG) patients and 952 controls evaluated 22 SNPs across 13 candidate genes identified from RA and SLE studies. The strongest finding was a protective four-SNP IRF5 haplotype (rs2004640_G/rs60344245_del/rs2070197_T/rs10954213_G) with reduced WG risk (p=0.0000897, OR 0.73, 95% CI 0.62-0.85). SNPs in TNFAIP3 and CDK6 also showed nominally significant associations, suggesting WG shares some genetic risk factors with other autoimmune diseases.

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 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.