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From SNPedia

Geno Mag Summary
(G;G) 0.1 normal; 0.9x decreased risk for rheumatoid arthritis
(G;T) 2.2 1.4x increased risk for SLE
(T;T) 2.5 1.4x increased risk for SLE
ReferenceGRCh38.p7 38.3/150
is asnp
is mentioned by
dbSNP (classic)rs2004640
1000 genomesrs2004640
GWAS Ctlgrs2004640
Max Magnitude2.5

rs2004640, a SNP in the IRF5 gene in chromosomal region 7q32.1, is one of several SNPs associated with systemic lupus erythematosus (SLE). This association has been observed in multiple populations (Caucasian, Asian, and African-Americans).

The association was first noted in two relatively large studies of Caucasian patients.[PMID 15657875, PMID 16642019]

In ~600 Korean SLE patients, the odds ratio for the rs2004640(T) risk allele was 1.44 (CI: 1.34-1.55, overall p=1.85x10e-23). The rs2004640-T/rs2280714-T haplotype involved in both the alternative splice donor site and the elevated expression of the IRF5 protein also had a highly significant association with SLE (pooled p=2.11x 10e-16).[PMID 17389033OA-icon.png]

[PMID 18288123] Reconfirmed for African-Americans

[PMID 17166181] Reconfirmed in ~370 female Caucasian patients

[PMID 17189288OA-icon.png] Reconfirmed in ~380 UK SLE families

[PMID 18311811] Pooled data from two populations (Japanese and Korean) were combined to determine that the rs2004640(T) allele frequency was significantly increased in SLE patients (p = 8.3 x 10-5).

[PMID 18063667] A variant located 64 bp upstream of the first untranslated exon (exon 1A), consisting of a 5 bp insertion/deletion CGGGG (rs77571059), may be the causative SNP in this region that is most responsible for increasing SLE risk.

[PMID 18843785] In a Korean population, rs2004640 was associated with both the anti-CCP Ab-positive (odds ratio 1.47, CI: 1.15-1.88, pcorr = 0.01) and SE-positive group (odds ratio 1.54, CI: 1.14-2.09, pcorr = 0.03) forms of rheumatoid arthritis. Combined analysis pooling 3 independent cohorts yielded an association with an odds ratio of 1.21, CI: 1.07-1.38, pooled p = 0.0031 in a dominant model.

[PMID 19116937] rs2004640(T;T) is associated with susceptibility to systemic sclerosis in a study of ~800 French Caucasian patients, with an odds ratio of 1.58 (CI: 1.18 - 2.11, p trend 0.002).

[PMID 19228650] A meta-analysis comprising 5 case-control studies, totaling 6,582 rheumatoid arthritis cases and 5,375 controls, concluded that several IRF5 gene SNPs were indeed (still) significantly associated with the disease. The rs2004640(G) allele was associated with a slight protective effect (odds ratio 0.9, CI: 0.85-0.96, p = 0.002).

[PMID 19479858] Of 3 IRF5 SNPs studied, the rs2280714(A) SNP (and not this one) had the strongest association (odds ratio 1.42, CI: 1.15-1.75) in Japanese SLE patients.

[PMID 18285424OA-icon.png] Association with multiple sclerosis (along with several other SNPs) was observed after combining data from Swedish and Spanish case/control studies and a Finnish trio study.


[PMID 19644887] STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis

[PMID 19644876] Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome

[PMID 19877059] BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4

[PMID 20980283] The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype

[PMID 21239750] Association of IRF5 Polymorphisms with Susceptibility to Macrophage Activation Syndrome in Patients with Juvenile Idiopathic Arthritis


[PMID 21471993] Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferon? therapy in multiple sclerosis

[PMID 22544929OA-icon.png] IRF5 Risk Polymorphisms Contribute to Interindividual Variance in Pattern Recognition Receptor-Mediated Cytokine Secretion in Human Monocyte-Derived Cells.

[PMID 17133578] Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis.

[PMID 17158136OA-icon.png] IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis.

[PMID 17393452] Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus.

[PMID 17412832OA-icon.png] Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus.

[PMID 17615072OA-icon.png] The ITGAV rs3738919-C allele is associated with rheumatoid arthritis in the European Caucasian population: a family-based study.

[PMID 17940599OA-icon.png] Assembly of inflammation-related genes for pathway-focused genetic analysis.

[PMID 18045485OA-icon.png] The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes.

[PMID 18050197OA-icon.png] Association of an IRF5 gene functional polymorphism with Sjogren's syndrome.

[PMID 18200047] IFN-regulatory factor 5 gene variants interact with the class I MHC locus in the Swedish psoriasis population.

[PMID 18438842] Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis.

[PMID 18668568OA-icon.png] Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients.

[PMID 18752149] Association of IRF5 gene polymorphisms with rheumatoid arthritis in a Tunisian population.

[PMID 19043711] Association between the rs2004640 functional polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta-analysis.

[PMID 19109131OA-icon.png] Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo.

[PMID 19302705OA-icon.png] Testing for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in a European family-based study.

[PMID 19591781OA-icon.png] The search for lupus biomarkers.

[PMID 19778912OA-icon.png] Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.

[PMID 19849816OA-icon.png] Genetics of rheumatic disease.

[PMID 19918036] Lack of association between IRF5 gene polymorphisms and biopsy-proven giant cell arteritis.

[PMID 19918037OA-icon.png] Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.

[PMID 19923204] Genetic background of systemic sclerosis: autoimmune genes take centre stage.

[PMID 20080916] Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells.

[PMID 20112383OA-icon.png] Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus.

[PMID 20137629] [Relationship between polymorphism sites of IRF5, TLR-9 and SLE patients in Shandong Han population].

[PMID 20231204] Phenotype-haplotype correlation of IRF5 in systemic sclerosis: role of 2 haplotypes in disease severity.

[PMID 20383147OA-icon.png] Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.

[PMID 20439292] Genetic variants in the prediction of rheumatoid arthritis.

[PMID 20479942OA-icon.png] Genetic risk factors in lupus nephritis and IgA nephropathy--no support of an overlap.

[PMID 20639879OA-icon.png] Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis.

[PMID 20652065OA-icon.png] Interferon alpha in systemic lupus erythematosus.

[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 21834935] A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus.

[PMID 21898142] Association of IRF5 polymorphisms with susceptibility to hemophagocytic lymphohistiocytosis in children.

[PMID 22179739] Interferon regulatory factor 5 gene polymorphism confers risk to several rheumatic diseases and correlates with expression of alternative thymic transcripts.

[PMID 23073787] Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis: a meta-analysis

[PMID 23372721OA-icon.png] The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis

[PMID 23392701] Association of rs10954213 polymorphisms and haplotype diversity in interferon regulatory factor 5 with systemic lupus erythematosus: A meta-analysis

[PMID 23801380] Association of the IRF5 rs2004640 polymorphism with rheumatoid arthritis: a meta-analysis

[PMID 24350899] Molecular Effects of Autoimmune-Risk Promoter Polymorphisms on Expression, Exon Choice, and Translational Efficiency of Interferon Regulatory Factor 5

[PMID 23288367] Interferon regulatory factor 5 polymorphisms in sarcoidosis.

[PMID 25036352] Association between IRF5 polymorphisms and autoimmune diseases: a meta-analysis

[PMID 24116155OA-icon.png] Two functional variants of IRF5 influence the development of macular edema in patients with non-anterior uveitis

Risk Rs2004640(T;T)
Alt Rs2004640(T;T)
Reference Rs2004640(G;G)
Significance Other
Disease Systemic lupus erythematosus 10 Rheumatoid arthritis
Variation info
Gene IRF5
CLNDBN Systemic lupus erythematosus 10 Rheumatoid arthritis
Reversed 0
HGVS NC_000007.13:g.128578301G>T
CLNSRC OMIM Allelic Variant
CLNACC RCV000003564.1, RCV000003565.1,

[PMID 26294277] Genetic association and interaction between the IRF5 and TYK2 genes and systemic lupus erythematosus in the Han Chinese population

[PMID 31916109OA-icon.png] Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease.