rs41295061 — IL2RA

Regulatory variant in the IL2RA locus altering LEF1 transcription factor binding and soluble IL-2 receptor levels — the C allele increases type 1 diabetes susceptibility while the minor A allele raises Graves' disease risk

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IL2RA rs41295061 — The Immune Thermostat Variant

The interleukin-2 receptor alpha chain (IL-2Rα, also called CD25) sits at a critical junction in immune regulation. When IL-2 binds to its receptor on T cells, it triggers proliferation of both effector T cells that drive immune responses and regulatory T cells (Tregs) that shut them down. The balance between these two arms determines whether your immune system attacks pathogens appropriately or turns on your own tissues. rs41295061 is a regulatory region variant11 regulatory region variant
Located at chr10:6,072,697 GRCh38 in the IL2RA locus, affecting transcription factor binding rather than protein sequence in the IL2RA locus that influences this fundamental balance.

The Mechanism

A proteome-wide allele-specific binding screen22 proteome-wide allele-specific binding screen
Butter et al. PLoS Genetics 2012, PMID 23028375 found that the transcription factor LEF1 binds approximately 8 times more strongly to the minor A allele at rs41295061 than to the common C allele. LEF1 is a downstream effector of the Wnt signaling pathway that regulates T cell development and survival. This differential binding suggests the A and C alleles create functionally different regulatory environments for IL2RA transcription. Separately, a functional study33 functional study
Qu et al. J Immunol 2009, PMID 19794070 showed that rs41295061 marks one major IL2RA susceptibility locus, while a nearby independent variant tagged by rs3118470 further reduces IL2RA expression through a distinct mechanism.

The net result of common C allele homozygosity is lower soluble IL-2RA levels in circulation. Fine-mapping of the IL2RA locus44 Fine-mapping of the IL2RA locus
Lowe et al. Nature Genetics 2007, PMID 17676041 found that T1D-risk IL2RA genotypes produce significantly lower concentrations of circulating soluble IL-2RA (p=6.28×10⁻²⁸), a biomarker that reflects regulatory T cell activity. Reduced IL-2 signaling through the IL-2Rα high-affinity complex impairs Treg maintenance, tilting the immune balance toward autoimmunity.

The Evidence

The association of rs41295061 with type 1 diabetes is among the strongest non-HLA genetic signals for this disease. A meta-analysis of 10 independent studies55 meta-analysis of 10 independent studies
Tang et al. J Cell Mol Med 2015, PMID 26249556 totaling 32,646 individuals identified rs41295061 as one of the three most associated IL2RA SNPs for T1D, alongside rs11594656 and rs2104286. The minor A allele showed a protective odds ratio of 0.67 (95% CI: 0.60–0.76), meaning the C allele homozygote is the T1D-risk genotype.

The same variant has opposing effects in Graves' disease (autoimmune hyperthyroidism). A study of 1,474 Graves' disease patients66 study of 1,474 Graves' disease patients
Chistiakov et al. Scand J Immunol 2011, PMID 21815908 found that the A allele confers increased Graves' risk (OR 1.43, p=0.001), with A allele carriers showing elevated soluble IL-2RA levels in both patients and healthy controls. This allele-specific direction reversal across autoimmune diseases is biologically plausible: the same IL-2 signaling axis can drive pathogenic immune responses in different directions depending on which immune cell populations dominate in each disease.

Beyond T1D and Graves' disease, rs41295061 shows modest associations with juvenile idiopathic arthritis77 juvenile idiopathic arthritis
Hinks et al. Arthritis Rheum 2009, PMID 19116909 (OR 0.80 for A allele, p=0.05) and ANCA-associated vasculitis88 ANCA-associated vasculitis
Carr et al. BMC Med Genet 2009, PMID 19265545 (p=0.0122), though these associations are weaker than the T1D signal. The IL2RA locus appears to influence broad immune dysregulation rather than a single disease-specific pathway.

Practical Implications

The CC genotype (the most common globally, ~83% of Europeans by Hardy-Weinberg estimate) is the T1D risk genotype. However, it is important to emphasize that T1D is a polygenic, multifactorial disease — HLA genotype alone accounts for ~50% of genetic risk, and rs41295061 is a contributing factor, not a deterministic predictor. The vast majority of CC homozygotes will never develop T1D. Monitoring for early signs of autoimmune disease is the most actionable response to this genotype.

The heterozygous AC genotype confers intermediate T1D risk reduction, and the rare AA homozygote is associated with meaningfully lower T1D susceptibility but modestly elevated Graves' disease risk.

For individuals with a family history of T1D, Graves' disease, or other autoimmune conditions, knowing rs41295061 status adds context to a genetic risk picture that should also include HLA typing, PTPN22 rs2476601, and CTLA4 rs3087243. IL2RA variants like this one are particularly relevant for understanding the IL-2 pathway's role in immune homeostasis.

Interactions

rs41295061 operates in the same IL2RA locus as rs2104286, the other major IL2RA T1D variant already in this database. These two variants have partially overlapping but independent effects: rs2104286 is an intronic variant with its own effect on IL2RA expression, while rs41295061 operates through a distinct regulatory mechanism involving LEF1 binding. Conditional regression analyses show rs3118470, a separate variant near rs41295061, confers additional independent risk after accounting for rs41295061 (p=5×10⁻³).

The IL2RA locus interacts functionally with PTPN22 rs2476601 (the R620W T-cell activation variant) and CTLA4 rs3087243 (the immune checkpoint variant). Both of those variants impair T-cell negative regulation through different mechanisms: PTPN22 reduces TCR signaling threshold while CTLA4 reduces co-stimulatory braking. Combined, these three regulatory pathway variants likely compound autoimmune susceptibility, though their joint effect has not been formally quantified in a multi-SNP interaction model.

Genotype Interpretations

What each possible genotype means for this variant.

AA T1D Protective Genotype Beneficial

Rare protective genotype; substantially lower type 1 diabetes susceptibility at this locus, though modestly higher Graves' disease risk

The AA genotype at rs41295061 is among the rarest common-variant configurations in the IL2RA locus. The mechanistic basis for T1D protection is believed to involve stronger LEF1 transcription factor binding (~8× affinity difference per the Butter 2012 proteome screen), supporting more robust IL2RA expression and higher Treg maintenance signaling. The elevated soluble IL-2RA in AA carriers mirrors this higher receptor turnover. Why this same configuration elevates Graves' risk is not fully resolved — one hypothesis is that higher IL-2 signaling in the thyroid-reactive lymphocyte compartment promotes the specific pattern of autoimmunity that characterizes Graves' rather than islet autoimmunity. Given the rarity of the AA genotype, published data are limited and effect estimates carry wider confidence intervals than for AC or CC.

AC T1D Partial Protection Intermediate

One protective A allele reduces T1D risk compared to CC; intermediate soluble IL-2RA levels

Heterozygous AC individuals produce intermediate levels of soluble IL-2RA compared to CC and AA homozygotes, consistent with an additive gene dosage effect on IL2RA regulatory activity. The net clinical picture for AC individuals is nuanced: partial T1D risk reduction and partial Graves' risk elevation relative to the CC reference. Given the opposing directional effects, the most relevant context is family history — if your family carries more T1D, your AC genotype is reassuring relative to CC; if your family carries more Graves' or other thyroid autoimmunity, the elevated Graves' signal of the A allele is worth noting. In absolute terms, both effects are modest and should be interpreted in the context of broader autoimmune genetic architecture (HLA, PTPN22, CTLA4).

CC T1D Risk Genotype High Risk

Common risk genotype for type 1 diabetes; reduced IL-2 signaling impairs regulatory T cell maintenance

The CC genotype at rs41295061 is associated with altered transcription factor binding (specifically, reduced LEF1 affinity compared to the A allele) and lower circulating soluble IL-2RA concentrations. Soluble IL-2RA reflects the shedding of the receptor's extracellular domain and is a surrogate marker for IL-2 pathway activity. Lower soluble IL-2RA in CC individuals is consistent with reduced Treg homeostatic signaling — regulatory T cells depend on IL-2 signaling for their maintenance and suppressive function.

This is a common-variant risk factor, not a Mendelian disease mutation. The incremental T1D risk from rs41295061 CC is modest in isolation; the clinical relevance is highest when this genotype co-occurs with high-risk HLA genotypes (DR3/4-DQ8), PTPN22 rs2476601 T allele, or CTLA4 rs3087243 G allele. Population-level, T1D lifetime incidence in Northern Europeans is approximately 0.4%, and IL2RA CC genotype might shift this estimate by a factor of 1.2–1.5× — still a rare absolute risk, but meaningful for family-history risk stratification.