IL1A rs6542095 — Inflammation at the Root of Endometriosis
The IL1A gene encodes 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 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
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 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 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.
Alla genotyper
No copies of the C risk allele — baseline endometriosis susceptibility at this IL1A locus
You carry two copies of the T allele at rs6542095. This is the most common genotype globally, present in approximately 48% of the population. At this IL1A regulatory locus, you carry no copies of the C allele that is associated with modestly elevated risk of moderate-to-severe endometriosis in large GWAS meta-analyses. This does not eliminate your risk of endometriosis — the disease is polygenic and strongly influenced by hormonal, immune, and environmental factors beyond this single locus. It does mean you do not carry additional inflammatory-pathway risk from this particular IL1A signal.
One copy of the C risk allele — modestly elevated endometriosis susceptibility via the IL-1α inflammatory pathway
You carry one copy of the C allele at rs6542095. Under the additive model, each C allele increases moderate-to-severe endometriosis risk by approximately 21% (OR ~1.21 per allele), so CT heterozygotes carry roughly 21% elevated baseline risk at this locus compared to TT carriers. Approximately 43% of people globally share this heterozygous genotype. The C allele at this IL1A regulatory locus is thought to modulate the expression of IL-1α, a pro-inflammatory cytokine that drives peritoneal inflammation, promotes adhesion of ectopic endometrial cells, and sustains the inflammatory environment that allows endometriosis implants to survive and grow. The association is specific to moderate-to-severe disease — the stage characterized by peritoneal adhesions and ovarian endometriomas.
Two copies of the C risk allele — elevated susceptibility to moderate-to-severe endometriosis via amplified IL-1α signaling
You carry two copies of the C allele at rs6542095. CC homozygotes carry approximately 46% elevated baseline risk of moderate-to-severe endometriosis at this locus compared to TT carriers (OR ~1.21² ≈ 1.46). Only about 9% of people globally carry this genotype, though it is substantially more common in East Asian populations where the C allele reaches ~71% frequency. The CC genotype at this IL1A regulatory locus is associated with the highest level of IL-1α-mediated inflammatory susceptibility among the three genotypes. The IL-1α cytokine drives key pathological processes in moderate-to-severe endometriosis: peritoneal inflammation, angiogenesis supporting implant survival, and formation of the fibrous adhesions that define advanced-stage disease. CC homozygotes may have higher baseline IL-1α expression or responsiveness, creating an inflammatory peritoneal environment more permissive to ectopic tissue establishment.