rs3783550 — IL1A

Intronic variant within IL1A (Interleukin-1 alpha) associated with endometriosis risk in Japanese and European GWAS; the G allele increases susceptibility by tagging IL-1α-driven peritoneal inflammation at a locus replicated across ancestries

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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.

Genotype Interpretations

What each possible genotype means for this variant.

TT Common Genotype Normal

No copies of the G risk allele — baseline endometriosis susceptibility at this IL1A intronic locus

You carry two copies of the T allele at rs3783550. This is the most common genotype globally, present in approximately 46% of the population. At this IL1A intronic locus, you carry no copies of the G allele that tags the IL-1α-associated endometriosis risk haplotype identified in Japanese and European GWAS studies.

This does not eliminate endometriosis risk — the disease is polygenic and strongly influenced by hormonal, immune, and environmental factors. It means you do not carry additional IL-1α inflammatory-pathway risk from this particular IL1A intronic signal.

GT Heterozygous Intermediate

One copy of the G risk allele — modestly elevated endometriosis susceptibility via the IL-1α inflammatory pathway

IL1A rs3783550 sits 41 base pairs before a splice junction within the IL1A gene (intronic position c.616-41). The variant does not alter the IL-1α protein but is part of a regulatory haplotype identified by the Sapkota 2015 meta-analysis that modulates IL1A expression. The risk haplotype (G allele) was tested as part of eight IL1A locus SNPs; all eight replicated in European imputed data with concordant direction of effect, and rs3783550 was one of three SNPs that also showed independent nominal association in a Japanese sample. The lead SNP rs6542095 reached genome-wide significance at OR 1.21 for moderate-to-severe endometriosis.

The East Asian population frequency pattern is notable: the G allele reaches ~72% frequency in East Asian populations versus ~21% in African populations, with European and South Asian populations at ~30% and ~28% respectively. This population stratification means GT heterozygotes are more common among East Asian women (many of whom actually carry GG homozygosity) and relatively unusual among African women.

GG Homozygous Risk High Risk

Two copies of the G risk allele — elevated susceptibility to moderate-to-severe endometriosis via amplified IL-1α inflammatory signaling

The GG genotype places you in the highest-risk category at the IL1A rs3783550 locus for inflammatory-pathway-mediated endometriosis susceptibility. The variant sits at the splice-adjacent intronic position c.616-41 within the IL1A gene, 41 bp upstream of a splice junction — a position where sequence variation can affect splicing efficiency, intronic regulatory elements, or long-range chromatin interactions with the gene promoter.

Mouse model data provide mechanistic support: IL-1R1 knockout and IRAK4 inhibition both significantly reduced endometriotic lesion volume and proliferative activity (Ki-67), confirming that IL-1 signaling causally sustains ectopic lesions rather than merely marking inflammation. Additionally, single-cell transcriptomic analysis of 21 patients identified M2 macrophages as the primary cell type through which IL1A risk variants influence disease — with anakinra (IL-1 receptor antagonist) dampening both pain and pro-angiogenic signaling in endometriosis-affected animals.

The genome-wide significant evidence anchors to the linked lead SNP rs6542095 (OR 1.21, p=3.43×10⁻⁸, Sapkota 2015), with rs3783550 tagging the same haplotype. The association is specific to moderate-to-severe (stage III/IV) endometriosis — the stage involving peritoneal adhesions, ovarian endometriomas, and deep infiltrating lesions — rather than mild peritoneal implants.