rs6542095 — IL1A IL1A rs6542095

IL1A rs6542095 — Inflammation at the Root of Endometriosis

The IL1A gene encodes Interleukin-1 alpha¹¹ Interleukin-1 alpha
IL-1α is a pro-inflammatory cytokine released from damaged cells that activates immune responses and promotes tissue remodeling, one of the most potent drivers of peritoneal inflammation in the body. In the context of endometriosis, IL-1α plays a central mechanistic role: it promotes adhesion of ectopic endometrial cells to the peritoneum, stimulates angiogenesis to nourish nascent implants, and recruits immune cells that paradoxically fail to clear the ectopic tissue. The rs6542095 variant near IL1A is the first genome-wide significant genetic link between the IL-1 inflammatory axis and endometriosis susceptibility.

The Mechanism

rs6542095 sits at chromosome 2, position 112,771,606 (GRCh38), approximately 2.3 kb upstream of the IL1A transcription start site (the gene is encoded on the minus strand, so this chromosomal distance places the variant in the 5' regulatory region). The functional consequence is classified as regulatory — the variant does not alter the IL-1α protein sequence, but rather is thought to influence IL1A promoter activity or transcriptional regulation, affecting how much IL-1α protein is produced in response to inflammatory stimuli.

IL-1α operates through a well-characterized pathway: upon cellular stress or damage, pre-IL-1α is released and binds the IL-1 receptor (IL-1R1), triggering NF-κB activation and a cascade of downstream inflammatory gene expression. In the peritoneal cavity of women with endometriosis, elevated IL-1α levels in peritoneal fluid²² elevated IL-1α levels in peritoneal fluid
Multiple studies have measured significantly higher IL-1 concentrations in the peritoneal fluid of women with active endometriosis compared to disease-free controls promote endometrial stromal cell survival, adhesion to mesothelial surfaces, and formation of the fibrous adhesions characteristic of advanced-stage disease. Genetic variants that upregulate IL1A expression would therefore be expected to amplify this inflammatory cascade and favor ectopic implant establishment.

The Evidence

The pivotal study was a meta-analysis of 3,908 endometriosis cases and 8,568 controls of European and Japanese ancestry³³ meta-analysis of 3,908 endometriosis cases and 8,568 controls of European and Japanese ancestry
Sapkota et al. Association between endometriosis and the interleukin 1A (IL1A) locus. Human Reproduction, 2015 that combined data from eight IL1A locus SNPs previously identified in small Japanese studies. The analysis found genome-wide significant association of rs6542095 with moderate-to-severe endometriosis (OR 1.21, 95% CI 1.13–1.29; p = 3.43 × 10⁻⁸), representing the first genome-wide significant evidence linking the IL-1 pathway to endometriosis susceptibility. Importantly, the association was restricted to moderate-to-severe disease (stages III/IV by revised American Fertility Society classification) — patients with mild endometriosis did not show a significant association. This stage-specificity aligns with the biology: IL-1α-driven peritoneal inflammation and adhesion formation are more characteristic of advanced-stage disease.

Independent replication was achieved in a Belgian cohort of 998 cases and 783 controls⁴⁴ Belgian cohort of 998 cases and 783 controls
Sapkota et al. Independent Replication and Meta-Analysis for Endometriosis Risk Loci. Twin Research and Human Genetics, 2015, where rs6542095 showed nominally significant association (p = 0.01 for grade B disease) and, when combined with the original dataset in meta-analysis, maintained genome-wide significance. A subsequent systematic review covering 35,022 endometriosis cases⁵⁵ systematic review covering 35,022 endometriosis cases
Cardoso et al. Systematic review of GWAS on susceptibility to endometriosis. EJOG Reproductive Biology, 2020 confirmed IL1A rs6542095 as one of five robustly replicated endometriosis susceptibility variants alongside WNT4, GREB1, FN1, and VEZT signals.

Replication has not been universal — a Polish cohort study did not find significant association in 315 cases — consistent with modest effect sizes that may be influenced by population composition and disease staging criteria.

Practical Actions

The C allele at rs6542095 is associated with elevated moderate-to-severe endometriosis susceptibility, not a diagnosis of endometriosis. The OR of 1.21 per C allele means CC homozygotes (two copies) carry approximately 1.46-fold elevated baseline risk at this locus compared to TT homozygotes. This is a meaningful but modest effect from a single variant. The most actionable implication is heightened vigilance for symptoms of moderate-to-severe endometriosis — precisely the stage that benefits most from early diagnosis before extensive adhesion formation occurs.

Because this variant specifically tags inflammatory-pathway susceptibility, it may also inform choices about managing peritoneal inflammation: progestin-based therapies reduce endometrial proliferation and can suppress IL-1-driven implant survival, and early laparoscopic excision removes the inflammatory foci before disease progresses.

Interactions

IL1B rs1143634 and IL1RN rs2234663: The IL-1 axis involves three proteins — IL-1α (encoded by IL1A), IL-1β (encoded by IL1B), and the IL-1 receptor antagonist (encoded by IL1RN) that competitively inhibits both. Women carrying both an IL1A risk allele (rs6542095-C) and a high-producing IL1B variant, or a low-producing IL1RN variant, may experience compounded peritoneal inflammation — the double burden of amplified IL-1 signaling with reduced natural counter-regulation. Formal compound-effect data are limited, but the pathway logic is well-established.

rs12700667 (near HOXA10/HOXA11): HOXA genes regulate endometrial differentiation and uterine receptivity. Risk alleles at the HOXA locus (rs12700667) combined with IL1A rs6542095-C could compound susceptibility through independent pathways — inflammatory implant survival (IL-1α) and defective endometrial patterning (HOXA).

rs1250248 (FN1): Fibronectin-1 mediates extracellular matrix remodeling and cell adhesion — both of which are promoted by IL-1α signaling in the peritoneum. Co-carriage of FN1 and IL1A risk alleles could synergize to favor ectopic tissue adhesion and invasion.