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 Evidence

The first signal at the IL1A locus came from a genome-wide association meta-analysis in Japanese women33 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 study44 follow-up study
Hata et al. 2013, J Hum Genet 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 controls55 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 in the European imputed data 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 women66 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 disequilibrium77 linkage disequilibrium
LD: the tendency of nearby variants to be inherited together on the same chromosomal segment with the missense variant rs17561 (Ala114Ser).

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.

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.

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.

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. 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.