rs10488631

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 extended UK genome-wide association study identified a novel rheumatoid arthritis susceptibility locus at 22q12 (rs1043099, P = 6.9 × 10⁻⁹, OR = 0.84) in 3,034 cases and 5,271 controls, and confirmed 16 previously known RA loci, strengthening evidence for genetic contributors to RA in the UK population.

A study of 1,115 UK rheumatoid arthritis patients receiving anti-TNF biologic therapy found that rs10919563 in the PTPRC gene was associated with improved treatment response (regression coefficient 0.19, 95% CI 0.09-0.37, P=0.04 for continuous DAS28 outcome; OR 0.62, 95% CI 0.40-0.95, P=0.03 for good EULAR response). Meta-analysis with a previous study strengthened evidence (P=5.13×10⁻⁵). Secondary analysis identified rs11594656 in IL2RA associated with good EULAR response (OR 1.47, P=0.02).

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 study examined 27 previously identified rheumatoid arthritis (RA) risk alleles in 556 autoantibody-positive African-American RA cases and 791 controls. Twenty-four of 27 SNPs showed consistent odds ratios between African-Americans and Europeans; three SNPs (CCR6 rs3093023, TAGAP rs394581, TNFAIP3 rs6920220) showed opposite directions of effect. A genetic risk score analysis indicated that African-American cases were significantly enriched for European RA risk alleles (p=0.00005), suggesting that RA genetic risk factors are largely shared across ancestry groups.

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 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 functional study examined four genetic variants in the IRF5 gene (rs2004640, rs10488631, rs10954213, and a CGGGG indel) in 44 Swedish SLE patients and 16 healthy controls. The risk haplotype (H2) was associated with significantly elevated IRF-5 transcript and protein expression in patient blood cells (p=0.0084 for total IRF-5). rs10488631 showed the only significant independent association with increased transcription from exon 1C (p=0.0155). Minigene assays demonstrated that rs2004640, the CGGGG indel, and type I interferons regulate IRF-5 expression.

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.

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.