rs4728142

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).

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 cross-sectional study of 1906 SLE patients found that European genetic ancestry is protective against lupus nephritis development. A 10% increase in European ancestry was associated with a 15% reduction in renal disease risk (OR 0.85, 95% CI 0.82-0.87, p=1.9×10^-30), independent of socioeconomic status and candidate genes including IRF5 (rs4728142), BLK (rs2736340), STAT4 (rs3024912), and ITGAM (rs9937837).

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.

A three-stage genetic association study of interferon pathway-related genes identifies multiple novel loci associated with systemic lupus erythematosus (SLE). The study evaluated 1,754 genes in two discovery/replication cohorts (939 SLE cases, 3,398 controls) with confirmation in an independent cohort. Novel confirmed associations include CD44 (rs507230, P = 3.98×10⁻¹², OR = 0.71), pleiotrophin/PTN (rs919581, P = 5.38×10⁻⁴), DNAJA1 (rs10971259, P = 6.31×10⁻³), and KPNA1 (rs6810306, P = 4.91×10⁻²).

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.

PhD thesis describing comprehensive genome-wide association studies of acute anterior uveitis (AAU) in European (2,752 cases, 3,836 controls) and East Asian (821 cases, 4,898 controls) populations. European descent GWAS identified HLA-B at genome-wide significance plus 11 suggestive loci (ERAP1, NOS2, MERTK). East Asian GWAS identified HLA-B and ERAP1 at genome-wide significance plus 12 suggestive loci (GPR68, RHBDD2). Mendelian randomization confirmed ERAP1 as functionally relevant and showed genetically predicted CRP levels positively associated with AAU risk.