rs7574865, a SNP in the third intron of the STAT4 gene, has been reported in a large study of Swedes to be associated with both rheumatoid arthritis (RA) and lupus (SLE). Among other studies, it has been confirmed in a meta-analysis of 8 studies totaling 7,381 patients and over 10,000 controls from both European and Asian populations.[PMID 20169389]
The risk allele (oriented to the dbSNP entry) is (T); the odds ratio associated the presence of a risk allele was 1.3 for rheumatoid arthritis and 1.55 for lupus (SLE). The paper states that, "Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis." [PMID 17804842]
A study of 124 Caucasian patients with primary Sjögren's syndrome, an autoimmune disease related to RA and SLE, also found the rs7574865(T) allele to be associated with higher risk for this condition (p=0.01). The GT genotype is associated with 1.42x and the TT with 2.28x odds. [PMID 18273036]
[PMID 18516230] associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p<10(-11)), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10(-13))
[PMID 18576330] The combined ORs for RA and SLE, respectively, were 1.27 (P = 8.4 x 10(-9)) and 1.61 (P = 2.1 x 10(-11)) for allele frequency distribution; these ORs in the Japanese were quite similar to those previously observed in the Caucasian population
[PMID 18576336] RA risk associated with rs7574865(T) allele was also found in studies of 923 Spanish, 273 Swedish, and 876 Dutch patients.
[PMID 18759272] A study of 2,776 Spanish subjects found that the rs7574865(T) allele was associated with rheumatoid arthritis, Crohn's disease, ulcerative colitis, and type-1 diabetes, but not with multiple sclerosis.
[PMID 19332627] Lack of Association Between STAT4 Gene Polymorphism and Biopsy-proven Giant Cell Arteritis
|Trait||Systemic lupus erythematosus|
|Title||Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX|
|Odds Ratio||NR NR|
[PMID 19479340] Association of STAT4 polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis
[PMID 19500629] STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous population of Crete, Greece
[PMID 19565500] Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis
[PMID 19404967] Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis
[PMID 19588142] Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a meta-analysis
[PMID 19644887] STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis
[PMID 19714582] Rheumatoid arthritis does not share most of the newly identified systemic lupus erythematosus genetic factors
[PMID 19737838] A haplotype in STAT4 gene associated with rheumatoid arthritis in Caucasians is not associated in the Han Chinese population, but with the presence of rheumatoid factor
[PMID 19644876] Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome
|Trait||Systemic lupus erythematosus|
|Title||Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus|
|Odds Ratio||1.51 [1.43-1.61]|
[PMID 20039785] The Protein Tyrosine Phosphatase, Non-Receptor Type 22 R620W Polymorphism Does Not Confer Susceptibility to Psoriasis in the Genetic Homogeneous Population of Crete
[PMID 19877059] BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4
[PMID 19684152] Cigarette smoking, STAT4 and TNFRSF1B polymorphisms, and systemic lupus erythematosus in a Japanese population
[PMID 20176035] Association of signal transducer and activator of transcription 4 genetic variants with extra-intestinal manifestations in inflammatory bowel disease
[PMID 20438790] STAT4 polymorphism in a Chinese Han Population with Vogt-Koyanagi-Harada syndrome and Behcet's disease
|Title||A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility|
|Odds Ratio||1.17 [1.10-1.25]|
|Title||Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk lock|
|Odds Ratio||1.16 [1.10-1.23]|
[PMID 20498205] Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers
[PMID 21163111] Variation in STAT4 is associated with systemic lupus erythematosus in Chinese Northern Han population
[PMID 21237270] Polymorphisms in STAT4 Increase the Risk of acute renal allograft rejection in the Chinese population
[PMID 21418779] Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders
|Title||Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci|
|Odds Ratio||None None|
|Title||Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti-dsDNA Autoantibody Production|
|Odds Ratio||1.4100 [1.21-1.63]|
[PMID 21683716] Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in Northwestern Chinese Han population
|Title||Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.|
|Odds Ratio||1.3800 [1.27-1.50]|
[PMID 21968398] TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey
[PMID 22133489] The polymorphisms of T cell-specific TBX21 and STAT4 genes may contribute to the susceptibility of Chinese individuals to aplastic anemia
[PMID 22173230] A meta-analysis of the association between cytokine gene polymorphisms and systemic sclerosis
[PMID 22483685] Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population
[PMID 22714917] Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis
[PMID 17932559] Association of STAT4 with rheumatoid arthritis in the Korean population.
[PMID 18432273] STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians.
[PMID 18434327] Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility.
[PMID 18579578] A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5.
[PMID 18794853] Common variants at CD40 and other loci confer risk of rheumatoid arthritis.
[PMID 18803832] Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region.
[PMID 19019891] STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk.
[PMID 19109131] Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo.
[PMID 19116934] The chromosome 7q region association with rheumatoid arthritis in females in a British population is not replicated in a North American case-control series.
[PMID 19120275] STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes.
[PMID 19225526] Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese.
[PMID 19286670] The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.
[PMID 19287509] Genome-wide association study of determinants of anti-cyclic citrullinated peptide antibody titer in adults with rheumatoid arthritis.
[PMID 19333953] High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups.
[PMID 19371230] STAT4 is not associated with type 2 diabetes in the genetically homogeneous population of Crete.
[PMID 19442287] Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study.
[PMID 19445664] Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls.
[PMID 19458352] Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
[PMID 19591781] The search for lupus biomarkers.
[PMID 19605742] STAT4 single nucleotide polymorphism, rs7574865 G/T, as a risk for antiphospholipid syndrome.
[PMID 19674979] Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis.
[PMID 19838195] A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.
[PMID 19849816] Genetics of rheumatic disease.
[PMID 19923204] Genetic background of systemic sclerosis: autoimmune genes take centre stage.
[PMID 20018027] Conditional analysis of the major histocompatibility complex in rheumatoid arthritis.
[PMID 20018035] A combinatorial approach for detecting gene-gene interaction using multiple traits of Genetic Analysis Workshop 16 rheumatoid arthritis data.
[PMID 20018049] Evaluation of an optimal receiver operating characteristic procedure.
[PMID 20153791] STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: a replication study.
[PMID 20169177] Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.
[PMID 20353580] Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort.
[PMID 20360187] Influence of STAT4 polymorphism in primary Sjogren's syndrome.
[PMID 20439292] Genetic variants in the prediction of rheumatoid arthritis.
[PMID 20444755] Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment.
[PMID 20454450] Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn's disease and early disease onset.
[PMID 20652065] Interferon alpha in systemic lupus erythematosus.
[PMID 20722033] The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1.
[PMID 21149496] NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.
[PMID 21167895] Association of genetic variations in the STAT4 and IRF7/KIAA1542 regions with systemic lupus erythematosus in a Northern Han Chinese population.
[PMID 21379322] Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes.
[PMID 21922340] Combined influence of genetic and environmental factors in age of rheumatoid arthritis onset.
[PMID 22569826] Abnormal Genetic and Epigenetic Changes in Signal Transducer and Activator of Transcription 4 in the Pathogenesis of Inflammatory Bowel Diseases.
|qualified_impact||Insufficiently evaluated pathogenic|
|Trait||Systemic lupus erythematosus|
|Title||Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis.|
|Odds Ratio||1.48 [1.335-1.634]|
|Trait||Primary biliary cirrhosis|
|Title||Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.|
|Odds Ratio||1.35 [1.19-1.52]|
|Trait||Systemic lupus erythematosus|
|Title||Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians.|
|Trait||Hepatocellular carcinoma (hepatitis B virus related)|
|Title||Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma.|
|Odds Ratio||1.21 [1.14-1.28]|
[PMID 23727609] Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a Chinese population
[PMID 23755762] STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population
[PMID 23912645] Association of STAT4 rs7574865 with Susceptibility to Systemic Lupus Erythematosus in Iranian Population
[PMID 24023622] Analysis of Gender Differences in Genetic Risk: Association of TNFAIP3 Polymorphism with Male Childhood-Onset Systemic Lupus Erythematosus in the Japanese Population
[PMID 23360093] Association study of STAT4 polymorphisms and type 1 diabetes in Northeastern Chinese Han population
[PMID 24059108] [Signal transducer and activator of transcription 4 gene polymorphisms associated with dilated cardiomyopathy in Chinese Han population]