rs3134883 — IL2RA

Intronic IL2RA variant independently associated with rheumatoid arthritis risk and part of the IL-2 receptor locus haplotype architecture modulating Treg-driven immune tolerance

See your personal result for IL2RA

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

IL2RA rs3134883 — A Second Independent Signal at the Autoimmune Thermostat

The IL2RA locus11 IL2RA locus
IL2RA on chromosome 10p15.1 encodes CD25, the alpha subunit of the high-affinity interleukin-2 receptor, essential for Treg development and maintenance is one of the most replicated non-HLA autoimmune susceptibility regions in the human genome. While rs2104286 is the most commonly cited variant at this locus, fine-mapping studies have established that multiple independent genetic signals coexist in the same region, each tagging distinct regulatory effects on IL-2 receptor expression and immune tolerance. rs3134883 is one of these independent signals — it anchors a five-variant haplotype block with its own disease associations.

The Mechanism

rs3134883 sits in an intron of IL2RA at chromosome 10, position 6,058,762 (GRCh38). The IL2RA gene lies on the minus strand, but the variant is always reported in plus-strand notation (G/A) as per the GRCh38 reference. It is not a coding change; rather, it is an intronic tag SNP22 intronic tag SNP
Intronic variants can influence gene expression through effects on transcription factor binding, RNA splicing, chromatin accessibility, or enhancer activity within introns.

The five-variant protective haplotype H5 — comprising rs3134883 (G allele), rs3118470, rs7072793, rs4749955, and rs12251307 — tags a protective IL2RA regulatory state33 tags a protective IL2RA regulatory state
The H5 haplotype was in perfect LD (r²=1.0) with the minor allele of ss52580101 in CEU populations, a variant associated with altered IL-2RA expression and soluble receptor shedding.

The Evidence

The Type I Diabetes Genetics Consortium study44 Type I Diabetes Genetics Consortium study
5,003 T1D-affected sib-pair families from a large international consortium, 69 SNPs spanning ~88 kb of IL2RA established rs3134883's place in the IL2RA haplotype architecture. The protective H5 haplotype carrying the G allele showed OR 0.699 (95% CI 0.602–0.811, p=3.2×10⁻⁵) for T1D protection. Crucially, rs3134883 retained independent statistical significance (p=4.29×10⁻³) after conditioning on the full H5 haplotype, suggesting it tags both haplotype-level and potentially position-specific regulatory effects.

For rheumatoid arthritis, rs3134883 is among the lead variants at the IL2RA locus in large-scale GWAS. A multi-ancestry RA GWAS55 multi-ancestry RA GWAS
Ishigaki et al. meta-analysis across European and East Asian populations, confirming multiple independent IL2RA signals with OR ~1.1 per A allele at rs3134883 confirmed the A allele at rs3134883 reaches genome-wide significance (p as low as 2×10⁻¹⁵ in the Ha et al. 2020 analysis) with OR approximately 1.1 per allele for seropositive RA. This effect is independent from rs2104286, reflecting the well-established multi-signal architecture66 multi-signal architecture
Fine-mapping of IL2RA identifies at least three independent association signals affecting T1D and MS through different molecular pathways of the IL2RA locus.

In vitiligo, a GWAS of Chinese Han participants77 GWAS of Chinese Han participants
6,857 vitiligo cases and 12,025 controls in a two-stage replication study confirmed the 10p15.1 locus — encompassing rs3134883 — as a susceptibility locus (OR 1.11, p=1.01×10⁻⁵), demonstrating that the IL2RA risk haplotype extends beyond European-ancestry autoimmune diseases. Lymphocyte count modulation by rs3134883 has also been reported in GWAS (p=2×10⁻²¹), consistent with the locus's role in regulating the size and activation state of T-cell populations.

Practical Implications

The A allele at rs3134883 marks a modest but independently established increase in autoimmune disease susceptibility across multiple diseases — RA, T1D, and vitiligo. Its effect is additive: AA homozygotes carry approximately twice the incremental risk of a single A allele.

For RA specifically, knowledge of IL2RA genotype has implications for treatment response monitoring. IL2RA variation influences lymphocyte counts and immune activation set-points, potentially affecting responsiveness to biologics targeting the TNF or IL-6 pathways. Carriers of the A allele should be attentive to early joint symptoms (morning stiffness, bilateral symmetric joint pain) that may signal early RA before structural damage develops.

Interactions

Interactions with CTLA4 rs3087243 (immune checkpoint) and PTPN22 rs2476601 (T-cell activation threshold) are biologically plausible as parallel pathways to Treg and effector T-cell dysregulation.

Genotype Interpretations

What each possible genotype means for this variant.

GG Protective Haplotype Normal

Two copies of the protective G allele — favorable IL2RA haplotype for autoimmune risk

You carry two copies of the G allele at rs3134883. This configuration is associated with lower autoimmune disease risk relative to A allele carriers. About 57% of Europeans carry this genotype. Your IL2RA contribution to autoimmune susceptibility from this variant is at the lowest level.

AG One Risk Allele Intermediate

One A allele modestly elevates autoimmune susceptibility through altered IL2RA haplotype

The RA signal at rs3134883 reaches genome-wide significance (p=2×10⁻¹⁵ to 3×10⁻¹³ in large GWAS) and is independent of the better-known rs2104286 variant at the same locus, confirming that this variant captures non-redundant information about IL2RA haplotype architecture. Vitiligo association in Chinese Han populations (OR 1.11) and lymphocyte count modulation (p=2×10⁻²¹) further support the locus's broad role in immune calibration.

AA Two Risk Alleles High Risk

Two A alleles — elevated autoimmune risk from the IL2RA susceptibility haplotype

The RA associations for rs3134883 are among the strongest at the non-HLA IL2RA locus in multi-ancestry GWAS (p=2×10⁻¹⁵ for any RA, p=3×10⁻¹³ for seropositive RA). The A allele also influences lymphocyte counts (p=2×10⁻²¹), consistent with broader effects on immune cell homeostasis. In East Asian populations, rs3134883 contributes to vitiligo susceptibility (OR 1.11), extending the locus's relevance across ethnicities and disease types.