ANRIL at 9p21.3 — A Cell Cycle Gatekeeper in Endometriosis
The 9p21.3 region of chromosome 9 is one of the most functionally
complex loci in the human genome. It encodes three tumor suppressors
— p16INK4a, p14ARF (encoded by CDKN2A) and p15INK4b (encoded by CDKN2B) | These proteins are cyclin-dependent kinase inhibitors that halt cell-cycle progression and trigger senescence
— and is also home to ANRIL (Antisense Non-coding RNA in the INK4 Locus) | Also designated CDKN2B-AS1 or CDKN2BAS — a long non-coding RNA transcribed on the antisense strand overlapping CDKN2A and CDKN2B,
a molecular rheostat for how readily cells stop dividing and become
senescent. rs1537377 is an independent endometriosis-risk signal at
this locus, distinct from but in partial linkage disequilibrium with
the index CDKN2BAS variants identified in Japanese GWAS.
The Mechanism
ANRIL regulates its neighboring tumor suppressors CDKN2A/B through
epigenetic silencing. It recruits the
PRC2 complex | Polycomb Repressive Complex 2 — a histone methyltransferase that adds H3K27me3 marks, compacting chromatin and silencing genes
to deposit H3K27me3 on the CDKN2A/B promoters, and the PRC1 complex
to maintain repression through histone H2A ubiquitination. The net
effect is that ANRIL expression level determines how effectively
cells keep their p15/p16 senescence checkpoint suppressed — allowing
continued proliferation.
In endometriosis, this biology is directly relevant: ectopic
endometrial cells implant at peritoneal and ovarian sites and must
evade normal senescence and apoptosis to survive and proliferate in
an ectopic environment. Functional fine-mapping at the 9p21.3
endometriosis locus
showed that protective alleles drive stronger chromatin interaction with the ANRIL promoter | Borghese et al. 2016 — Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. PLOS Genetics.
via TCF7L2 and EP300 binding, increasing ANRIL transcription. More
ANRIL means more CDKN2A/B silencing, which counterintuitively appears
protective against endometriosis in this regulatory context, suggesting
that the disease-associated haplotype disrupts normal ANRIL-mediated
cell cycle regulation in endometrial stromal cells.
Consistent with this model, elevated ANRIL expression has been
independently found in ectopic endometriotic tissue relative to normal
ovarian epithelium
with expression levels increasing progressively from ASRM stage II to stage IV | Endometriosis Prognosis Correlates With Elevated Expression of LncRNA-ANRIL. Obstetrics & Gynecology International, 2025.,
suggesting that ANRIL dysregulation tracks disease severity rather
than simply marking disease presence.
The Evidence
The first GWAS to implicate CDKN2BAS in endometriosis was conducted in
1,907 Japanese women with endometriosis and 5,292 controls | Uno et al. 2010 — A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nature Genetics..
The lead SNP rs10965235 reached p=5.57×10⁻¹² (OR 1.44) and mapped to
intron 16 of CDKN2BAS. rs1537377 represents a distinct signal at this
locus identified in subsequent trans-ethnic meta-analysis.
In the
Nyholt et al. (2012) GWAS meta-analysis of 4,604 cases and 9,393 controls | Genome-wide association meta-analysis identifies new endometriosis risk loci. Nature Genetics.
across Japanese and European samples, rs1537377 at 9p21.3 emerged as
genome-wide significant in analyses restricted to moderate-to-severe
European cases (OR approximately 1.15, p<5×10⁻⁸). The larger
Rahmioglu et al. (2014) meta-analysis of 11,506 cases and 32,678 controls | Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight GWAS and replication datasets. Human Reproduction Update.
confirmed the association at p=1.5×10⁻⁸, and noted that eight of nine
identified loci — including 9p21.3 — showed stronger effect sizes
among Stage III/IV cases, consistent with a role in facilitating
ectopic tissue invasion and persistence.
Belgian replication
in 998 cases and 783 controls | Sapkota et al. 2015 — Independent Replication and Meta-Analysis for Endometriosis Risk Loci. Twin Research and Human Genetics.
confirmed rs1537377 among nine loci retaining genome-wide significance
in European populations through meta-analysis, and noted that coding
variants within CDKN2B-AS1 near rs1537377 also showed nominally
significant associations.
Practical Actions
For women carrying one or two C alleles, the endometriosis risk signal
at 9p21.3 is most actionable in two ways: earlier diagnostic vigilance
for endometriosis (particularly moderate-to-severe presentations), and
awareness that the 9p21.3 locus is shared with multiple other diseases
including cardiovascular disease and several cancers, so any management
of the locus's senescence pathway has broad implications.
The shared biology of 9p21.3 with ANRIL's role across diseases also means
that interventions targeting cellular senescence — such as senolytic
compounds that clear p16-positive cells — have theoretical relevance
to the ectopic cell survival biology at this locus, though direct
evidence in endometriosis specifically is not yet available.
Interactions
rs10965235 (CDKN2BAS): The index Japanese GWAS SNP at the 9p21.3
endometriosis locus. rs1537377 and rs10965235 tag the same chromosomal
region but represent partially independent signals in trans-ethnic
meta-analysis; combined carrier status would represent the full 9p21.3
endometriosis haplotype burden.
rs2811712 (CDKN2BAS): Another regulatory variant in ANRIL that
primarily associates with physical aging and functional impairment through
the same CDKN2B/p16 pathway. The two variants operate in the same ANRIL
regulatory context but through different aspects of the locus.
rs1333049 (9p21.3 CAD locus): The primary coronary artery disease
SNP at 9p21.3. Women with both the endometriosis-risk C allele at
rs1537377 and the CAD-risk C allele at rs1333049 carry risk haplotypes
at both faces of this pleiotropic locus, warranting combined
cardiovascular and reproductive monitoring.
Alla genotyper
Typical endometriosis risk at the 9p21.3 locus
You carry two copies of the T allele at rs1537377. About 31% of people globally share this genotype (higher in Europeans at ~37%). At this particular 9p21.3 endometriosis locus, TT represents the lower-risk genotype — your ANRIL regulatory balance at this variant is not shifted toward the endometriosis-associated state. This does not eliminate endometriosis risk, which depends on many genetic and environmental factors, but this specific signal is not elevated for you.
One copy of the 9p21.3 endometriosis risk allele
You carry one C and one T allele at rs1537377. About 49% of people globally share this genotype, making it the most common. Genome-wide association studies have identified the C allele as a risk factor for endometriosis, with each C allele increasing odds by approximately 9–15%. As a CT carrier you have a moderate elevation in susceptibility at this locus. The effect is strongest for moderate-to-severe (ASRM Stage III/IV) endometriosis, where cell cycle dysregulation in ectopic tissue appears most relevant.
Two copies of the 9p21.3 endometriosis risk allele
You carry two copies of the C allele at rs1537377. About 20% of people globally share this genotype. Each C allele adds approximately 9–15% to endometriosis odds (OR ~1.09–1.15 per allele), so CC homozygotes carry the highest risk at this locus — roughly 1.2–1.3× the baseline odds compared to TT. Genome-wide meta-analyses including up to 11,506 cases confirm the association, and effect sizes are notably stronger for ASRM Stage III/IV disease, suggesting this locus particularly influences severe, invasive endometriosis.