rs3783550 — IL1A

IL1A rs3783550 — An Intronic Inflammatory Susceptibility Variant

The IL1A gene encodes Interleukin-1 alpha¹¹ Interleukin-1 alpha
IL-1α is a pro-inflammatory cytokine released primarily from stressed or damaged cells; it binds the IL-1 receptor (IL-1R1) to activate NF-κB and drive inflammatory gene expression throughout the body, one of the body's most potent alarm signals for tissue damage. In endometriosis, IL-1α plays a central pathological role: it promotes adhesion of ectopic endometrial fragments to the peritoneal surface, stimulates blood vessel formation to nourish nascent implants, and activates tissue-remodeling enzymes that allow ectopic tissue to invade surrounding structures. rs3783550 is an intronic variant within IL1A that was identified as part of the first genome-wide significant evidence connecting the IL-1 inflammatory axis to endometriosis susceptibility.

The Mechanism

rs3783550 sits at chromosome 2, position 112,775,308 (GRCh38), within an intron of IL1A — specifically 41 base pairs before a splice junction (c.616-41 in coding-strand notation). Because IL1A is encoded on the minus strand of chromosome 2, the plus-strand alleles G and T correspond to C and A on the coding strand. The variant does not alter the IL-1α protein sequence. Its intronic location suggests it may act as a regulatory element²² regulatory element
Intronic variants can influence gene expression through effects on splicing efficiency, intronic enhancers, or long-range chromatin interactions with the gene promoter that modulates how much IL-1α is produced in response to inflammatory signals such as retrograde menstruation.

IL-1α operates through a well-characterized cascade: upon cell stress, pre-IL-1α is released and binds IL-1R1, triggering NF-κB-mediated transcription of downstream inflammatory mediators including IL-6, IL-8, VEGF (vascular endothelial growth factor), and matrix metalloproteinases. In the peritoneal cavity of women with endometriosis, elevated IL-1α promotes endometrial stromal cell survival on mesothelial surfaces, vascularization of new implants, and the fibrous adhesions characteristic of stage III/IV disease. A variant that amplifies IL1A expression — even modestly — would be expected to tip the peritoneal environment toward ectopic tissue establishment.

Recent work identifying M2 macrophages as major mediators of germline endometriosis risk³³ M2 macrophages as major mediators of germline endometriosis risk
Ochoa et al. 2025 Advanced Science; integrated data from 450,000 individuals and 350,000 single-cell transcriptomes across 21 patients placed IL1 signaling at the center of genetic susceptibility — and specifically showed that expression of IL1A is regulated by risk variants at this locus, providing functional support for the GWAS signal.

The Evidence

rs3783550 was characterized as part of a meta-analysis of 3,908 endometriosis cases and 8,568 controls⁴⁴ meta-analysis of 3,908 endometriosis cases and 8,568 controls
Sapkota et al. Association between endometriosis and the interleukin 1A (IL1A) locus. Human Reproduction, 2015 combining European and Japanese cohorts. Among eight IL1A locus SNPs tested, rs3783550 was one of three that showed nominal association with endometriosis in an independent Japanese sample (p < 0.05) and one of eight that successfully replicated in European imputed data (p < 0.014 with concordant direction of effect). The lead SNP in this region, rs6542095, reached genome-wide significance (OR 1.21, 95% CI 1.13–1.29; p = 3.43 × 10⁻⁸) for moderate-to-severe endometriosis. rs3783550 is in linkage disequilibrium with rs6542095, tagging the same IL1A risk haplotype.

The biological plausibility of this locus is reinforced by multiple lines of evidence. IL-1 receptor knockout and IRAK4 inhibition significantly reduced endometriotic lesion volume and Ki-67 expression in mouse models⁵⁵ IL-1 receptor knockout and IRAK4 inhibition significantly reduced endometriotic lesion volume and Ki-67 expression in mouse models
Kato et al. 2019 Frontiers in Immunology, demonstrating that IL-1 signaling causally drives lesion growth rather than being a secondary marker of inflammation. IL-1 receptor antagonist anakinra dampened pain and pro-angiogenic signaling in endometriosis-affected mice⁶⁶ IL-1 receptor antagonist anakinra dampened pain and pro-angiogenic signaling in endometriosis-affected mice
Ochoa et al. 2025, and an early clinical study showed peritoneal IL-1 concentrations sufficient to impair embryo development were present specifically in endometriosis patients⁷⁷ were present specifically in endometriosis patients
Fakih et al. 1987 Fertility and Sterility.

The evidence is classified as moderate — robust GWAS replication across two ancestries, clear biological mechanism, but individual per-SNP effect sizes for rs3783550 are not reported separately from the broader locus signal.

Practical Actions

The G allele at rs3783550 tags the IL1A endometriosis risk haplotype. Carrying G alleles does not diagnose endometriosis — it is one of many genetic contributors to a polygenic, hormonally and immunologically complex condition. The actionable implication is heightened alertness to symptoms that suggest moderate-to-severe (stage III/IV) disease, which is where the IL-1α-driven inflammatory pathology is most prominent: peritoneal adhesions, ovarian endometriomas, and deep infiltrating lesions.

Because the IL-1 pathway is the mechanistic link here, approaches that modulate peritoneal inflammation — including progestin-based hormonal suppression and timely laparoscopic excision of established lesions — directly target the biology implicated by this variant.

Interactions

rs6542095 (IL1A): rs3783550 is in linkage disequilibrium with rs6542095, the lead IL1A locus SNP associated with endometriosis at genome-wide significance. Together they tag the same IL1A risk haplotype; carrying risk alleles at both is consistent with inheritance of the same high-IL-1α regulatory block rather than two independent effects.

IL1B rs1143634 and IL1RN rs2234663: The IL-1 signaling axis involves both IL-1α (IL1A) and IL-1β (IL1B), which share the same receptor (IL-1R1) and act synergistically. The natural counter-regulator, IL-1 receptor antagonist (encoded by IL1RN), competitively inhibits both. Women carrying IL1A G-alleles alongside high-producing IL1B variants or low-producing IL1RN variants may experience amplified net peritoneal IL-1 signaling — a compounded inflammatory environment potentially more permissive to ectopic tissue establishment than any single variant alone.