rs7574865

This association study of 6039 European subjects (1020 HCC cases, 5019 controls including prospective cohorts) identified PNPLA3 rs738409 (OR=3.91, p=1.14E-09) and TM6SF2 rs58542926 (OR=1.79, p=0.001) as significant risk variants for hepatocellular carcinoma in alcoholic liver disease patients, with a dose-dependent additive effect. PNPLA3 rs738409 was also associated with HCC developed on non-fibrotic liver (OR=2.19, p=0.007), suggesting a direct carcinogenic role independent of cirrhosis.

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.

This case-control study of 155 children with childhood-onset rheumatoid arthritis (CORA) and 684 healthy controls examined whether five RA-associated genetic variants also confer susceptibility to CORA. Variants in PTPN22 (rs2476601, OR 1.61), STAT4 (rs7574865, OR 1.41), and TNFAIP3 (rs10499194, OR 0.60) showed significant associations with CORA in a similar magnitude and direction as in adult RA. A weighted genetic risk score (wGRS) incorporating these variants plus HLA alleles was strongly associated with CORA risk (p<2×10⁻¹⁶), with individuals in the top quintile having 11.66-fold increased odds compared to the bottom quintile.

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

Two SNPs in VKORC1 (rs9934438 and rs9923231) were identified as genetic risk factors for systemic lupus erythematosus (SLE) in Asian populations. In discovery cohort (263 SLE cases, 357 controls), both SNPs showed strong associations (OR=2.40-2.45, p=6.1×10^-9 to 2.4×10^-9), which were confirmed in a larger replication cohort (1496 cases, 993 controls) with OR=1.53-1.54 (p=4.3-5.1×10^-6), and remained significant after ancestry adjustment (OR=1.34, p=0.0029-0.0032).

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 case-control study of 675 Chinese female SLE patients and 679 controls found that STAT4 rs7582694 is strongly associated with systemic lupus erythematosus susceptibility (OR=0.68, 95% CI: 0.58-0.79, P=1.13×10⁻⁶). However, no significant associations were found between rs7582694 and any of the 11 SLE clinical subphenotypes examined, including nephritis, arthritis, autoantibodies, and neuropsychiatric disorders.

Study of 507 Spanish rheumatoid arthritis patients examining genetic and environmental factors influencing age of disease onset. Shared epitope, anti-CCP antibodies, and higher education were individually associated with younger onset (P=0.033, 0.004, <0.0001). Patients carrying all three genetic markers (HLA-SE, PTPN22 rs2476601, STAT4 rs7574865) showed disease onset 9.56 years earlier than those with none (P=0.004). Combined genetic and environmental factors demonstrated additive effects on age at RA onset.

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.

This review synthesizes genome-wide association studies (GWAS) identifying host genetic factors affecting hepatitis B virus (HBV) infection outcomes. HBV persistence is predominantly associated with HLA genes (HLA-DP, HLA-DQ, HLA-C with OR 0.46-2.31) and immune-related genes including CFB, NOTCH4, CD40, UBE2L3, TCF19, and EHMT2. HBV persistence and hepatitis B vaccine nonresponse share overlapping genetic bases with HLA variants, while genetic risk factors for advanced liver diseases (cirrhosis, hepatocellular carcinoma) are largely distinct.

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 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.

This population genetics study characterized the worldwide distribution of the common 32-kb LCE3C-LCE3B deletion (LCE3C_LCE3B-del) at chromosome 1q21, a variant associated with psoriasis and other autoimmune disorders. Using array comparative genomic hybridization (aCGH) and PCR-based genotyping across 31 worldwide populations (768 individuals), the authors found that the deletion is common in most populations but shows significant frequency variation. The highest deletion frequency (75%) was found in the Pima population, while Sub-Saharan African populations had lower frequencies (27-35%). The tag SNP rs4112788 shows variable linkage disequilibrium with the CNV across populations, suggesting that allele frequency differences may result from genetic drift rather than natural selection.

This cohort study of 2,324 subjects with inflammatory polyarthritis tested 17 rheumatoid arthritis (RA) susceptibility SNPs for association with all-cause and cardiovascular disease (CVD) mortality. Carriage of the CCL21 risk allele rs2812378 was associated with increased CVD mortality (HR 1.33, 95% CI 1.01-1.75) and all-cause mortality (HR 1.40, 95% CI 1.04-1.87), with the strongest effects observed in anti-CCP antibody-positive patients with both the CCL21 risk alleles and shared epitope (SE) alleles (all-cause HR 3.20, 95% CI 1.52-6.72; CVD HR 3.73, 95% CI 1.30-10.72). SNPs at the TRAF1/C5 locus were not significantly associated with mortality in this study.

This case-control association study of juvenile idiopathic arthritis (JIA) in 809 JIA cases and 3,521 controls identified susceptibility loci shared with other autoimmune diseases. Three novel loci were identified: PTPN2 (strongest signals rs7234029, p=7.19×10⁻¹¹, OR=1.59; rs1893217, p=3.48×10⁻⁸, OR=1.52; rs2542151, p=3.05×10⁻⁷, OR=1.45), COG6 (rs7993214, p=3.98×10⁻³, OR=0.79), and ANGPT1 (rs1010824, p=4.93×10⁻³, OR=0.77). Four previously reported JIA loci were confirmed: PTPN22, STAT4, C12orf30, and IL2-IL21. Odds ratios ranged from 1.20 to 1.65 in meta-analysis of initial and independent replication cohorts (n=1,015 cases and 1,568 controls).

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.

Meta-analysis of 15 studies (16,088 RA patients, 16,509 controls) confirms that the STAT4 rs7574865 T allele is associated with rheumatoid arthritis susceptibility across ethnic groups (overall OR=1.271, 95% CI=1.197-1.350, p<0.001). The association was significant in both Europeans (OR=1.300) and Asians (OR=1.216), with T allele prevalence varying ethnically from 21.4% (European) to 32.0% (Asian) in control populations.

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 found that genetic variants in TNFAIP3 (rs10499194, OR 0.74; rs6920220, OR 1.3), STAT4 (rs7574865, OR 1.24), and C12ORF30 (rs17696736, OR 1.2) loci previously associated with other autoimmune diseases are also significantly associated with juvenile idiopathic arthritis, supporting shared genetic susceptibility among clinically distinct autoimmune phenotypes.

A large case-control study of 4,374 SLE cases and 4,860 controls from multiple racial/ethnic groups identified strong genetic associations between multiple SNPs in the STAT4 gene and systemic lupus erythematosus (SLE), with the strongest association at rs10168266 (p=1.38×10⁻¹⁵ in Europeans, combined p=7.02×10⁻²⁵). Multiple significant haplotypes spanning the STAT4 gene were found across European, Asian-Korean, Hispanic, and African American populations, with conditional analyses suggesting rs10168266 explains the primary haplotypic association. In contrast, STAT1 showed only weak suggestive associations.

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 case-control study attempted to replicate a reported association between rs11761231 on chromosome 7q and female rheumatoid arthritis susceptibility. While initial analysis in North American samples showed some evidence of association with two SNPs (rs11761231 p=0.0076 and rs11765576 p=0.019 in NARAC), these associations disappeared after correction for population stratification using principal components analysis (EIGENSTRAT), emphasizing the critical importance of accounting for population structure in genetic association studies.

Two independent candidate gene association studies identified SNPs in TBX21 and STAT4 as significant risk factors for systemic sclerosis in North American whites. TBX21 rs11650354 (TT genotype) conferred 3.37-fold increased risk in recessive mode (P=1.4×10⁻¹⁵, combined N=902 cases/4,745 controls), while STAT4 rs11889341 A allele increased risk 1.29-fold in dominant mode (P=2.4×10⁻⁵, combined N=1,039 cases/3,322 controls). Gene-gene interaction analysis revealed synergistic effects on SSc susceptibility with altered Th1/Th2 cytokine profiles.

PhD thesis examining immune system dysfunction in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Multiple chapters present immunological and cellular studies investigating interferon signaling, neutrophil extracellular traps, B cell activation, dendritic cell subsets, and genetic associations including STAT4 rs7574865, BLK, BANK1, and IRF5 polymorphisms in APS.

This multi-population case-control replication study examined the STAT4 polymorphism rs7574865 in 2,072 rheumatoid arthritis (RA) patients and 2,474 controls across Spain, Sweden, and The Netherlands. The T allele of rs7574865 showed significant association with RA risk with combined effect size OR 1.25 (95% CI 1.13-1.37, P = 9.79 × 10^-6). Meta-analysis across all published populations confirmed the association with OR 1.25 (95% CI 1.19-1.33, P = 1 × 10^-5).

This study identified associations between interferon regulatory factor 5 (IRF5) haplotypes and rheumatoid arthritis in a large subgroup of patients, similar to patterns previously found in systemic lupus erythematosus. IRF5 haplotypes represent a significant genetic risk factor for RA susceptibility.

This association study examined STAT4 polymorphism rs7574865 in 3,567 Japanese RA cases and 591 SLE cases across three independent case-control cohorts. The T allele showed significant association with both RA (OR=1.27, P=8.4×10⁻⁹) and SLE (OR=1.61, P=2.1×10⁻¹¹) susceptibility, with effect sizes comparable to those observed in Caucasian and Korean populations, establishing STAT4 as a common genetic risk factor for autoimmune diseases across racial groups.

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 review examines slowly progressive type 1 diabetes mellitus (SPIDDM), also known as latent autoimmune diabetes in adults (LADA), discussing its pathogenesis, diagnostic markers, and genetic associations. Key findings include T-cell-mediated insulitis and pseudoatrophic islets characteristic of type 1 diabetes, absence of amyloid deposition seen in type 2 diabetes, and identification of multiple genetic susceptibility loci including HLA haplotypes, PTPN22 rs2476601, INS rs689, CTLA4, TCF7L2 rs7903146, ZMIZ1 rs12571751, SH2B3 rs7310615, and PFKFB3 rs1983890. GAD autoantibodies and HLA genotypes are important risk factors for beta-cell failure progression.