rs1537377 — CDKN2BAS CDKN2B-AS1 rs1537377

Regulatory variant in the ANRIL long non-coding RNA at the 9p21.3 locus; the C allele independently increases endometriosis susceptibility, with stronger effects in moderate-to-severe disease stages

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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)11 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)22 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 complex33 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 promoter44 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 IV55 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 controls66 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 controls77 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 controls88 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 controls99 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.

Genotype Interpretations

What each possible genotype means for this variant.

TT Typical Risk Normal

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.

CT One Risk Allele Intermediate

One copy of the 9p21.3 endometriosis risk allele

The 9p21.3 locus where rs1537377 sits within the ANRIL long non-coding RNA, a regulator of the CDKN2A/B tumor suppressors that control cellular senescence. The C allele at rs1537377 is associated with altered ANRIL expression regulation — functional fine-mapping at this locus has shown that protective alleles bind transcription factors TCF7L2 and EP300 more avidly, driving stronger ANRIL expression through chromatin interactions. The risk haplotype disrupts this regulatory circuit in ways that may reduce the normal senescence checkpoint in ectopic endometrial stromal cells, facilitating their survival and expansion outside the uterus.

Multiple meta-analyses including up to 11,506 cases and 32,678 controls have confirmed this association, and the effect is notably stronger in severe disease (Stage III/IV), suggesting the 9p21.3 signal particularly influences disease progression and invasiveness rather than initial implantation alone.

CC Two Risk Alleles High Risk

Two copies of the 9p21.3 endometriosis risk allele

As a CC homozygote, you carry the full 9p21.3 endometriosis-risk dose. The locus acts through ANRIL — the long non-coding RNA that epigenetically regulates the CDKN2A/B tumor suppressors p15INK4b and p16INK4a. Functional studies show that the risk haplotype at this locus weakens chromatin interactions at the ANRIL promoter, potentially reducing ANRIL transcription in ways that relax the senescence checkpoint in ectopic endometrial cells. Ectopic lesions that fail to undergo appropriate senescence or apoptosis can invade deeper tissue planes, driving Stage III/IV disease. Elevated ANRIL expression in ectopic tissue has been shown to correlate with disease stage, indicating that dysregulation of this circuit tracks disease severity.

The 9p21.3 locus is also the strongest genetic signal for coronary artery disease in Europeans (primarily through rs10757278 and rs1333049). While rs1537377 is primarily an endometriosis signal, it tags the same haplotype block, and concurrent risk at this locus for both reproductive and cardiovascular outcomes is worth tracking as you age.

This genetic risk is one of multiple factors that contribute to endometriosis. Family history, hormonal environment, immune function, and other genetic loci all play roles. The 9p21.3 signal explains a small portion of variance in disease; not everyone with CC will develop endometriosis, and many with TT will.