rs10167914 — IL1A IL1A Endometriosis Susceptibility Variant

A regulatory tag SNP in the IL1A/IL1B locus on chromosome 2q13; the G allele increases endometriosis risk (OR 1.12) and correlates with elevated IL-1 alpha expression, driving peritoneal inflammation and ectopic lesion establishment.

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The IL-1 Alpha Locus: Inflammation at the Root of Endometriosis

Endometriosis — where endometrial-like tissue grows outside the uterus — affects an estimated 10% of reproductive-age women and is driven as much by immune dysfunction as by hormonal disruption. This variant sits within a dense inflammatory gene cluster on chromosome 2q13 that encodes six members of the interleukin-1 family11 interleukin-1 family
IL-1 is a family of pro-inflammatory cytokines that coordinate immune responses and tissue remodelling, including IL-1 alpha (IL1A) and IL-1 beta (IL1B). Genetic variation here has been consistently linked to endometriosis risk across diverse populations.

The Mechanism

The rs10167914 variant does not change an amino acid; it sits in the regulatory landscape surrounding IL1A and IL1B and influences how much IL-1 alpha the body produces in peritoneal tissue. The G allele is associated with higher local IL-1 alpha expression. IL-1 alpha, in turn, directly stimulates matrix metalloproteinase-1 (MMP-1)22 matrix metalloproteinase-1 (MMP-1)
an enzyme that breaks down the extracellular matrix, enabling ectopic cells to invade surrounding tissue, recruits inflammatory cells to the peritoneum, and sustains the chronic low-grade inflammation that allows endometriotic implants to establish, survive, and proliferate. G-allele carriers thus have a molecular environment more permissive to lesion growth — not through oestrogen alone, but through an IL-1-mediated inflammatory loop.

The Evidence

The strongest signal comes from a large meta-analysis by Sapkota et al.33 meta-analysis by Sapkota et al.
Sapkota Y et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun, 2017 combining 17,045 endometriosis cases with 191,596 controls. rs10167914-G reached p=1×10⁻⁹ with an odds ratio of 1.12 (95% CI 1.08–1.15), a replicable, genome-wide-significant effect. An earlier targeted study Sapkota et al. 201544 Sapkota et al. 2015
Sapkota Y et al. Association between endometriosis and the interleukin 1A (IL1A) locus. Hum Reprod, 2015 confirmed IL1A locus signals in both European and Japanese samples, with rs6542095 reaching OR 1.21 for moderate-to-severe disease.

A detailed functional analysis by Gajbhiye et al. 201855 Gajbhiye et al. 2018
Gajbhiye R et al. Genetic Variation at Chromosome 2q13 and Its Potential Influence on Endometriosis Susceptibility Through Effects on the IL-1 Family. Reprod Sci, 2018 mapped the 500 kb region around rs10167914 and found that the locus spans 21 transcripts including six IL-1 family genes, supporting a regulatory role whereby risk variants alter expression across this entire cytokine network rather than affecting a single gene.

Protein-level confirmation comes from Hudelist et al. 200566 Hudelist et al. 2005
Hudelist G et al. Interleukin 1alpha and tissue-lytic MMP-1 are elevated in ectopic endometrium. Hum Reprod, 2005: IL-1 alpha staining was significantly higher in endometriotic lesions than in matched eutopic endometrium (p<0.001), with co-expression of MMP-1, the matrix-degrading enzyme it induces.

Practical Actions

For women carrying one or two G alleles, the actionable terrain involves managing IL-1 pathway activity and reducing the peritoneal inflammatory load. Long-chain omega-3 fatty acids (EPA and DHA) downregulate IL-1 alpha production by shifting eicosanoid biosynthesis toward less pro-inflammatory prostaglandins. This is a mechanism-specific intervention, not generic anti-inflammatory advice — the same shift does not occur with short-chain ALA from plant oils.

In clinical settings, IL-1 receptor antagonism (anakinra, canakinumab) is being explored for endometriosis. Women with confirmed or suspected endometriosis who carry the G allele have a biological rationale to discuss IL-1 pathway modulation with a specialist, particularly if standard hormonal therapies have been inadequate.

Interactions

The IL1A locus does not operate in isolation. IL-1 alpha signalling amplifies oestrogen- driven lesion survival — rs10167914-G carriers who also carry variants reducing oestrogen catabolism (e.g. CYP1B1 or CYP19A1 variants) may face a compounded inflammatory-hormonal milieu. Similarly, variants affecting NF-κB activation (TNF-α locus, NFKB1) or the prostaglandin pathway (PTGS2/COX-2) share mechanistic overlap with IL-1 signalling in endometriotic tissue. No compound action is proposed here — these interactions require dedicated literature support rather than pathway inference alone.

Genotype Interpretations

What each possible genotype means for this variant.

AA Typical IL-1 Activity Normal

No elevated IL-1 alpha risk for endometriosis at this locus

The IL1A/IL1B cluster on chromosome 2q13 regulates peritoneal inflammation. The AA genotype is linked to baseline IL-1 alpha expression without the upregulatory effect observed with the G allele. This does not confer absolute protection from endometriosis — oestrogen-driven and other immune mechanisms operate independently — but this particular inflammatory amplifier is not elevated.

AG One Risk Allele Intermediate

Mildly elevated endometriosis risk via increased IL-1 alpha activity

IL-1 alpha is a pro-inflammatory cytokine that drives matrix metalloproteinase-1 (MMP-1) production in peritoneal stromal cells. MMP-1 degrades the extracellular matrix, facilitating implantation and survival of ectopic endometrial cells. Carrying one G allele creates a peritoneal environment that is modestly more permissive to lesion establishment.

The effect size (OR 1.12) is modest individually, but endometriosis is polygenic — this variant combines additively with other susceptibility alleles across the genome. Women with unexplained pelvic pain, dysmenorrhea, or subfertility should be aware that this locus specifically implicates the IL-1 inflammatory pathway, which is distinct from (and additive with) oestrogen-driven mechanisms.

GG Two Risk Alleles High Risk

Higher endometriosis susceptibility from elevated IL-1 alpha activity at this locus

The GG genotype creates maximal regulatory drive toward IL-1 alpha overexpression in the peritoneal microenvironment. IL-1 alpha at elevated concentrations stimulates MMP-1 production, enabling ectopic endometrial cells to degrade surrounding connective tissue and establish implants. It also sustains macrophage activation and prostaglandin E2 synthesis, contributing to both lesion persistence and the cyclical inflammatory pain characteristic of endometriosis.

Importantly, OR 1.12 per allele is the GWAS-derived population estimate. Individual risk depends on interactions with other loci, oestrogen metabolism variants, immune background, and environmental exposures. GG at rs10167914 is a meaningful signal in a polygenic risk context, not a deterministic marker.