rs2004640

This functional genetic study examined 183 fibroblast strains from systemic sclerosis (SSc) patients and controls to identify SNP-trait associations with extracellular matrix gene expression in response to silica stimulation. SNP rs58905141 in TNFAIP3 (6q23.3) was consistently associated with MMP3 and MMP1 dose-response expression with 3.6 to 12.7-fold changes, remaining genome-wide significant in meta-analysis across Caucasian, African American, and Hispanic cohorts. Two other SSc-associated loci, IL2RA and ITGAM, also showed significant associations with MMP expression in silica-stimulated fibroblasts.

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 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 six case-control studies (4,818 cases, 4,316 controls) examining the IRF5 rs2004640 polymorphism and rheumatoid arthritis risk. The rs2004640-T allele was associated with significantly increased rheumatoid arthritis risk in the dominant genetic model (OR=1.14, 95% CI 1.05-1.25, p=0.003). In stratified analysis, associations were significant in Caucasians (T/T vs G/G: OR=1.25, p=0.03) and Asians (dominant model: OR=1.14, 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.

This review article updates the genetics of systemic sclerosis (SSc), a multifactorial autoimmune disease. Key findings include identification of multiple susceptibility genes through candidate studies (STAT4 rs7574865, PTPN22 rs2476601, CD226 rs763361, TNFAIP3 rs5029939, and others) and genome-wide association studies revealing loci at HLA, STAT4, CD247, TNPO3/IRF5, and novel regions (TNIP1, RHOB). A large GWAS (N=2,296 cases/5,171 controls) identified HLA-DQB1 (rs6457617) as the strongest association and replicated CD247 rs2056626. Gene-gene interaction studies demonstrated additive effects of STAT4, IRF5, and NLRP1 variants on disease susceptibility.

A doctoral thesis investigating endothelin receptor antagonists (mainly bosentan) for primary prevention of pulmonary hypertension in systemic sclerosis patients. The study reviews genetic variants associated with systemic sclerosis and analyzes clinical outcomes of endothelin receptor antagonist treatment in a cohort of Spanish systemic sclerosis patients, with logistic regression analysis showing a protective effect of bosentan treatment (OR 2.2-4.1) against pulmonary hypertension development.

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 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 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 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.

A case-control study in 1,855 French Caucasians found that STAT4 rs7574865 is a genetic risk factor for systemic sclerosis (SSc) with OR=1.29 (P=0.001), with additive effects alongside IRF5 rs2004640. Individuals with ≥3 risk alleles had OR=2.72 for SSc and OR=1.97 for fibrosing alveolitis (pulmonary fibrosis).

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 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.

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.

This review discusses genetic and epigenetic mechanisms in autoimmune diseases using twin study evidence. While concordance in monozygotic twins indicates genetic involvement in rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, ankylosing spondylitis, and psoriasis, discordance between identical twins suggests that environmental factors and epigenetic modifications are also crucial. The paper highlights that genome-wide association studies explain only a portion of autoimmunity cases and that discordant monozygotic twins provide valuable models for understanding epigenetic dysregulation.

This meta-analysis of 12 studies (5,517 SLE cases, 6,445 controls) demonstrates a significant association between the IRF5 rs2004640 T allele and systemic lupus erythematosus susceptibility across multiple ethnic populations (OR 1.429, 95% CI 1.359–1.503, P < 0.001). The association remained significant in European (OR 1.436) and Asian (OR 1.305) populations separately. The T allele prevalence varied by ethnicity, ranging from 34.4% in Asians to 51.8% in Europeans.

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.

Retrospective case-control study of 222 systemic sclerosis patients with digital ulcers examining whether endothelin receptor antagonist bosentan reduces pulmonary hypertension risk. Bosentan treatment was associated with lower pulmonary hypertension incidence (14% vs 28% in controls, p<0.05) and better echocardiographic parameters in multivariate analysis.

This case-control and family-based association study found a strong genetic association between IRF5 polymorphisms and systemic lupus erythematosus (SLE) in Mexican patients. SNP rs2070197 showed the strongest association (P = 1.26 × 10⁻²¹) with an odds ratio of 3.19 for the risk allele, and homozygotes for the risk haplotype had an odds ratio of 10.46. Notably, the risk haplotype was significantly more frequent in healthy Mexican individuals compared to Europeans, and even higher in Mexican Indians, suggesting genetic admixture influences SLE susceptibility.

This review by van der Helm-van Mil and Huizinga examines genetic advances in rheumatoid arthritis (RA), emphasizing subclassification into ACPA-positive and ACPA-negative disease subtypes. ACPA-positive RA is associated with HLA-DRB1 shared epitope alleles, PTPN22 C1858T (rs2004640 region), C5-TRAF1 region variants, and other loci, while ACPA-negative RA shows distinct genetic associations including HLA-DR3 alleles. The authors argue these distinct genetic architectures support disease reclassification and suggest differential genetic mechanisms drive the two RA subsets.