What you carry at this position in your DNA and what research says about it.
Autoimmune Disease Risk: 7/10 evidence, 55 publications.
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Sample genotype (not yours): T/T
Higher Autoimmune Risk
Carrying two copies of the T allele is associated with a significantly higher risk of systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. This genotype promotes the maximum production of hyperactive interferon proteins.
What this genotype means: Significantly increased risk of systemic lupus erythematosus; Higher susceptibility to systemic sclerosis and rheumatoid arthritis; Maximum production of alternative, hyperactive IRF5 isoforms.
Sample genotype (not yours): G/G
Typical Autoimmune Risk
Carrying two copies of the G allele is associated with a typical risk of lupus and a slightly lower risk of rheumatoid arthritis. This common genetic profile does not create the hyperactive interferon splice variants linked to autoimmunity.
What this genotype means: Typical risk of systemic lupus erythematosus; Slightly lower risk of rheumatoid arthritis; Standard interferon regulatory factor 5 expression.
Sample genotype (not yours): T/G
Elevated Autoimmune Risk
Carrying one copy of the T allele increases the risk of developing systemic lupus erythematosus and rheumatoid arthritis. This genetic variant alters gene splicing, leading to higher levels of inflammatory interferon proteins.
What this genotype means: Approximately 1.4x increased risk for systemic lupus erythematosus; Increased susceptibility to rheumatoid arthritis; Elevated levels of inflammatory type I interferons.
Gene function and biological role
Gene Function: The IRF5 gene encodes interferon regulatory factor 5, a transcription factor that plays a critical role in the innate immune system. It is highly involved in the signaling pathways of toll-like receptors and the production of type I interferons [1]. These interferons are key signaling proteins that help coordinate the body's defense against viral infections [1]. However, abnormal regulation or overproduction of interferon-alpha can trigger the immune system to mistakenly attack the body's own tissues [2]. Consequently, genetic variations in IRF5 are frequently linked to various autoimmune conditions [3].
Variant Impact: The rs2004640 variant is a splice donor variant located in the IRF5 gene. The minor T allele alters the splicing process by creating an alternative 5-prime donor splice site in exon 1 [4]. This change allows the gene to express several unique, highly active isoforms of the IRF5 protein [4]. These alternative transcripts lead to elevated expression of IRF5 and increased secretion of type I interferons [1]. This heightened immune signaling increases susceptibility to autoimmune disorders like lupus and rheumatoid arthritis [3].
Key Insight: The risk-associated T allele creates a completely new genetic splice site that forces the gene to produce unique, hyperactive forms of the interferon protein.
Location: IRF5. Chromosome 7 · 7q32.1 · 128.9 Mb
Estimated prevalence by population
Global 22.8%; European 26.0%; African 17.3%; East Asian 7.8%; South Asian 25.7%; Americas 20.9%; Ashkenazi 37.9%; Finnish 26.5%; Middle Eastern 39.2%; Amish 24.0%.
Estimated TT genotype frequency.
Global 49.2%; European 50.0%; African 48.6%; East Asian 40.3%; South Asian 50.0%; Americas 49.6%; Ashkenazi 47.3%; Finnish 50.0%; Middle Eastern 46.8%; Amish 50.0%.
Estimated TG genotype frequency.
Global 28.0%; European 24.0%; African 34.1%; East Asian 51.9%; South Asian 24.3%; Americas 29.5%; Ashkenazi 14.7%; Finnish 23.5%; Middle Eastern 14.0%; Amish 26.0%.
Estimated GG genotype frequency.
Showing effects for T/T genotype
Immunity & Inflammation
Autoimmune Diseases
Lupus. Evidence: 5/10. Source: PMID 38724181. ~1.4x Increased Risk.
Rheumatoid Arthritis. Evidence: 7/10. Source: PMID 35470158. Increased Risk.
Systemic Sclerosis. Evidence: 6/10. Source: PMID 31916109. ~1.6x Increased Risk.
Cardiovascular & Metabolic
Blood Cell & Iron Traits
Plateletcrit. Evidence: 7/10. Source: PMID 39789286. Typical.
Showing effects for G/G genotype
Lupus. Evidence: 5/10. Source: PMID 38724181. Typical Risk.
Rheumatoid Arthritis. Evidence: 7/10. Source: PMID 35470158. ~10% Lower Risk.
Systemic Sclerosis. Evidence: 6/10. Source: PMID 31916109. Typical Risk.
Plateletcrit. Evidence: 7/10. Source: PMID 39789286. Higher.
Showing effects for T/G genotype
Systemic Sclerosis. Evidence: 6/10. Source: PMID 31916109. Increased Risk.
Plateletcrit. Evidence: 7/10. Source: PMID 39789286. Slightly Higher.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Two copies of the T allele ensure that both copies of the IRF5 gene utilize the alternative splice donor site, leading to the highest levels of unique, hyperactive protein isoforms [1]. This molecular shift results in the robust upregulation of type I interferons, which can trigger immune cells to attack healthy tissues [2]. Clinical studies consistently link this homozygous genotype to an approximately 1.4-fold to 1.6-fold increased risk of systemic lupus erythematosus [3]. It is also strongly associated with susceptibility to systemic sclerosis, particularly the subtype involving pulmonary fibrosis [4]. Additionally, this genetic profile is linked to a higher likelihood of developing rheumatoid arthritis [5]. Knowing this risk can encourage proactive discussions with a doctor about early signs of joint pain, skin rashes, or chronic fatigue.
Significantly increased risk of systemic lupus erythematosus; Higher susceptibility to systemic sclerosis and rheumatoid arthritis; Maximum production of alternative, hyperactive IRF5 isoforms.
Sample genotype: GG (Homozygous)
Standard splicing of the IRF5 gene occurs when two copies of the G allele are present, avoiding the generation of hyperactive interferon isoforms [1]. Multiple clinical studies show that this genetic profile is protective against rheumatoid arthritis, reducing the odds of developing the condition by about ten percent [2]. It is also associated with a baseline, typical risk for systemic lupus erythematosus and systemic sclerosis [3]. Because the immune system's interferon pathway operates at a normal level, there is no genetically driven elevation in autoantibody production from this locus [1]. Maintaining a healthy lifestyle and managing stress can further support balanced immune function.
Typical risk of systemic lupus erythematosus; Slightly lower risk of rheumatoid arthritis; Standard interferon regulatory factor 5 expression.
Sample genotype: TG (Heterozygous)
A single T allele introduces an alternative splice donor site in the IRF5 gene, which generates unique protein isoforms [1]. These alternative isoforms contribute to elevated expression of interferon regulatory factor 5 and higher levels of type I interferons in the blood [2]. Large-scale genetic analyses indicate that carriers of this single T allele face an approximately 1.4-fold increased risk of developing systemic lupus erythematosus [3]. The presence of this variant is also associated with a higher susceptibility to rheumatoid arthritis and systemic sclerosis [4]. While this genetic profile increases susceptibility, environmental triggers such as ultraviolet light exposure or viral infections are typically required to initiate autoimmune symptoms [2]. Discussing family history of autoimmune diseases with a healthcare provider can help contextualize this risk.
Approximately 1.4x increased risk for systemic lupus erythematosus; Increased susceptibility to rheumatoid arthritis; Elevated levels of inflammatory type I interferons.
Variants with shared genetic architecture
rs4728142 · IRF5 Gene · Chr 7 · Autoimmune Disease Risk
rs3757387 · IRF5 Gene · Chr 7 · Autoimmune Disease Risk
rs729302 · IRF5 Gene · Chr 7 · Autoimmune Disease Risk
Interferon alpha in systemic lupus erythematosus.
Association between IRF5 polymorphisms and autoimmune diseases: a meta-analysis.
A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus.
Association of the IRF5 rs2004640 polymorphism with rheumatoid arthritis: a meta-analysis.
The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.
Content updated August 2026.
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