rs2856836 — IL1A

3' UTR variant in IL1A (interleukin-1 alpha) associated with endometriosis susceptibility across multiple ethnic populations; one of eight replicated IL1A locus SNPs linked to the chronic pelvic inflammatory environment that promotes ectopic endometrial implantation.

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IL1A rs2856836 — Inflammation's Foothold: A 3'UTR Variant That Shapes Endometriosis Risk

The immune system is not a passive bystander in endometriosis — it is an active participant. Interleukin-1 alpha11 Interleukin-1 alpha
IL-1α: a pro-inflammatory cytokine produced chiefly by macrophages and monocytes; signals through the IL-1 receptor to activate NF-κB and trigger downstream inflammatory cascades is one of the most consistently elevated cytokines in the peritoneal fluid of women with endometriosis. The gene encoding IL-1α, IL1A, resides on chromosome 2q14.1 and harbors a cluster of common variants that have emerged from multiple genetic association studies as replicated susceptibility factors for the disease. Among these, rs2856836 — located in the 3' untranslated region of the IL1A transcript — is one of eight IL1A locus SNPs shown to replicate across both European and Japanese populations.

The Mechanism

rs2856836 is a 3' UTR variant22 3' UTR variant
variants in the 3' untranslated region can alter mRNA stability, translational efficiency, or microRNA binding sites, affecting how much protein the gene ultimately produces. It does not change the IL-1α amino acid sequence. On the plus (forward) strand the reference allele is A and the alternate allele is G; because IL1A is transcribed from the minus strand, published papers commonly describe this as a T/C variant in coding-strand notation (T=reference, C=risk). The G allele (plus strand) sits at position chr2:112,774,506 (GRCh38), 561 nucleotides into the 3' UTR of transcript NM_000575.5.

The functional consequence of this specific 3'UTR change has not been experimentally characterised in isolation. The broader IL1A endometriosis risk locus, however, has been functionally mapped in detail: expression quantitative trait locus (eQTL) analysis across ten tissue types33 expression quantitative trait locus (eQTL) analysis across ten tissue types
Ochoa et al. 2025, Adv Sci; PMC12591210 shows that risk variants at the IL1A locus are associated with decreased IL1A expression, and that M2 peritoneal macrophages — the cell type that lines the peritoneal cavity and governs immune tolerance of ectopic endometrial tissue — are the primary germline risk mediators at this locus. The IL1A/IL1B cytokines scored the highest correlation with endometriosis risk across myeloid subgroups (Spearman r=0.59). In the endometriosis-affected peritoneal environment, dysregulated IL-1 signaling may impair macrophage-mediated clearance of refluxed endometrial cells — the critical gatekeeping step that, when disrupted, allows retrograde tissue to implant and establish ectopic lesions.

The Evidence

The first signal at the IL1A locus came from a genome-wide association meta-analysis in Japanese women44 genome-wide association meta-analysis in Japanese women
Adachi et al. 2010, J Hum Genet; 696 cases + 825 controls in which four of the five top-ranked SNPs (P<10⁻⁵) clustered around IL1A, identifying it as a functional candidate gene. A follow-up study55 follow-up study
Hata et al. 2013, J Hum Genet of 901 Japanese cases and controls confirmed rs2856836 as one of four significantly associated IL1A variants (P=0.0014), alongside the missense variant rs17561 (Ala114Ser, OR=1.91 in validation). Cross-ethnic replication came from a meta-analysis of 3,908 cases and 8,568 controls66 meta-analysis of 3,908 cases and 8,568 controls
Sapkota et al. 2015, Hum Reprod; PMC4262465 spanning Australian, British, and Japanese cohorts, where all eight IL1A SNPs replicated at P<0.014 with concordant effect directions. For rs2856836 specifically, the meta-analysis yielded OR=1.09 (95% CI 1.02–1.16, P=7.15×10⁻³) across all endometriosis, and OR=1.12 (95% CI 1.04–1.22, P=4.29×10⁻³) for moderate-to-severe (grade B) disease.

A smaller population-specific case-control study in Iranian women77 Iranian women
Badie et al. 2020, Gynecol Endocrinol; 105 cases, 102 controls found a stronger effect for the G allele (coding-strand C) — OR=2.2 (95% CI 1.4–3.6, P=0.001) — with TC and CC genotypes independently significant (OR=3.1 and OR=2.3 respectively). This larger per-allele estimate likely reflects the smaller study size and possible founder effects in the Iranian population rather than a qualitatively different genetic architecture.

No ClinVar classification exists for rs2856836. The association signal is consistent with a moderate-evidence risk factor: replicated across multiple ethnic groups with clear dose-response, plausible biological mechanism, but short of genome-wide significance and lacking direct functional characterisation of this specific variant.

Practical Actions

The central implication of carrying one or two copies of the G allele is a modestly elevated inflammatory predisposition toward endometriosis. The individual risk increment per G allele is small in absolute terms (OR ~1.09–1.12 per allele in the large meta-analysis), and this variant should be interpreted in the context of the broader IL1A locus and other endometriosis risk SNPs. Women carrying the G allele who experience dysmenorrhea, cyclic pelvic pain, deep dyspareunia, or unexplained infertility should not normalize these symptoms — earlier gynecological evaluation shortens the diagnostic delay that averages 7–10 years.

The inflammatory basis of this association suggests that strategies targeting pelvic inflammation may be particularly relevant: NSAIDs, which block prostaglandin synthesis downstream of IL-1 signaling, are first-line for endometriosis-associated pain. No supplement or dietary intervention has been shown to specifically modulate IL1A expression or activity in peritoneal macrophages. The management decision — including hormonal therapy, surgical evaluation, or fertility preservation — rests with a gynecologist.

Interactions

rs2856836 is in linkage disequilibrium88 linkage disequilibrium
LD: the tendency of nearby variants to be inherited together on the same chromosomal segment with the other seven IL1A locus SNPs studied by Sapkota et al. (2015), including the genome-wide significant regulatory variant rs6542095 (OR=1.21 for moderate-to-severe endometriosis) and the missense variant rs17561 (Ala114Ser). These SNPs reside within a ~8 kb stretch of the IL1A gene. Carriers of risk alleles at multiple IL1A locus SNPs may accumulate greater susceptibility through haplotype effects, though the independent contribution of each variant has not been formally dissected. The functional eQTL evidence points to the entire locus region modulating IL1A expression in M2 peritoneal macrophages — the single causal variant within this cluster has not been definitively identified.

Genotype Interpretations

What each possible genotype means for this variant.

AA Common Genotype Normal

Common genotype — typical IL1A inflammatory tone at this locus

The AA genotype represents baseline IL1A expression regulation at this locus. Endometriosis is a polygenic, multifactorial condition — this result does not eliminate risk conferred by other variants, lifestyle factors, or family history. Other IL1A locus SNPs (notably rs6542095 and rs17561) have independent effects worth reviewing if endometriosis is a clinical concern.

AG One Risk Allele Intermediate

One copy of the IL1A risk allele — modestly elevated endometriosis susceptibility

rs2856836 is one of eight IL1A locus SNPs that replicate across multiple ethnic populations in the Sapkota et al. 2015 meta-analysis (PMID 25336714). All eight SNPs showed concordant direction and similar effect sizes, suggesting they tag a shared functional signal at the locus. The Iranian population study (Badie et al. 2020, PMID 31248297) found a larger effect in its 207-person cohort (OR≈3.1 for the heterozygous TC/AG genotype), though this study was substantially smaller and may reflect population-specific allele frequency distributions or founder effects.

The eQTL evidence indicates that the risk allele is associated with decreased IL1A expression in peritoneal macrophages — paradoxically, lower IL-1α output may impair the macrophage-mediated immune clearance of retrograde endometrial cells that normally prevents ectopic implantation (Ochoa et al. 2025, PMID 38811527).

GG Two Risk Alleles High Risk

Two copies of the IL1A risk allele — elevated endometriosis susceptibility at this locus

The GG homozygous genotype represents the highest genetic susceptibility at the rs2856836 position, accumulating two copies of the allele linked to altered IL1A expression in the peritoneal immune environment. The functional eQTL data from Ochoa et al. 2025 (PMID 38811527) suggests that risk alleles at the IL1A locus reduce IL1A expression in M2 peritoneal macrophages — the cells that normally clear retrograde endometrial debris. With two risk copies, this suppression of peritoneal immune surveillance may be more complete, creating a more permissive environment for ectopic tissue implantation.

rs2856836 is part of a cluster of eight IL1A locus SNPs (including the genome-wide significant rs6542095 and missense rs17561) that all show concordant risk direction. GG homozygotes at rs2856836 are likely to also carry risk alleles at the neighboring linked variants, magnifying the cumulative locus-level susceptibility. In the Sapkota 2015 meta-analysis (PMID 25336714), the grade B (moderate-to-severe) endometriosis effect was consistently stronger than for minimal/mild disease across all eight IL1A SNPs — suggesting this locus is particularly relevant to the more symptomatic, surgically-confirmed phenotype.

This result should be interpreted alongside the broader endometriosis genetic profile; multiple loci (WNT4, VEZT, CDKN2B-AS1, FN1) contribute independently to overall risk.