rs1537373 — CDKN2B-AS1 ANRIL T2D/Cardiovascular Variant

ANRIL at 9p21.3 — The Dual Diabetes and Heart Attack Locus

Deep inside chromosome 9 lies a short stretch of DNA — the 9p21.3 locus — that carries some of the most replicated disease associations ever discovered. Within this region sits ANRIL (antisense non-coding RNA in the INK4 locus), a long non-coding RNA that acts as a molecular volume knob for cellular senescence. Variants in ANRIL are associated, in the same region of the genome, with coronary artery disease, myocardial infarction, type 2 diabetes, intracranial aneurysm, glioma, and physical aging — a concentration of GWAS hits rare in the human genome¹¹ a concentration of GWAS hits rare in the human genome
Pasmant E et al. ANRIL, a long noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J. 2011..

rs1537373 is an intronic variant within the ANRIL gene itself (CDKN2B-AS1), positioned at chromosome 9, base 22,103,342 on the GRCh38 reference. It is one of several independent tag SNPs at this locus, each capturing a partially distinct signal. The T allele at rs1537373 is the risk allele for myocardial infarction and brain aneurysm, while the locus as a whole — through nearby variants in strong linkage disequilibrium — also confers type 2 diabetes susceptibility.

The Mechanism

ANRIL is transcribed antisense to three protein-coding genes packed tightly together at 9p21.3: CDKN2B (encoding p15INK4b), CDKN2A (encoding p16INK4a and p14ARF), and MTAP. p15 and p16 are cyclin-dependent kinase inhibitors²² cyclin-dependent kinase inhibitors
CDK inhibitors block CDK4 and CDK6, preventing phosphorylation of Rb and halting cell-cycle progression from G1 to S phase — the canonical senescence checkpoint that drive cellular senescence. As cells accumulate damage or age, rising p16 and p15 levels lock them in a permanent growth arrest — senescent "zombie" cells³³ senescent "zombie" cells
Senescent cells remain metabolically active but stop dividing, secreting pro-inflammatory cytokines (the SASP) that progressively damage surrounding tissue that fuel atherosclerosis and impair tissue regeneration.

ANRIL regulates CDKN2A/CDKN2B expression in cis by recruiting PRC2 (Polycomb Repressive Complex 2)⁴⁴ PRC2 (Polycomb Repressive Complex 2)
PRC2 deposits repressive H3K27me3 histone marks that silence nearby genes; loss of PRC2 recruitment allows CDKN2A/2B to be more highly expressed, accelerating senescence to silence the INK4 locus. Variants at rs1537373 alter the expression of specific ANRIL isoforms, shifting the balance toward either more or less CDKN2A/2B expression in vascular and pancreatic tissues. In vascular smooth muscle cells (VSMCs), elevated p16/p15 accelerates VSMC senescence and plaque-forming behavior, driving atherosclerosis. In pancreatic beta cells, the same pathway reduces proliferative capacity and total beta-cell mass over decades, impairing insulin production.

Notably, the cardiovascular and T2D-associated SNPs within the 9p21 locus are largely non-overlapping⁵⁵ the cardiovascular and T2D-associated SNPs within the 9p21 locus are largely non-overlapping
Kong et al. ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease. Front Endocrinol. 2018. PMID:30087655, suggesting distinct ANRIL isoforms and regulatory elements govern each disease phenotype — with rs1537373 primarily tagging the cardiovascular signal at this multi-trait locus.

The Evidence

The 9p21 locus entered the cardiovascular genetics literature with force in 2007. Helgadottir et al.⁶⁶ Helgadottir et al.
A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007. PMID:17478679 showed that approximately 21% of the population is homozygous for the risk variant at 9p21, and their estimated MI risk is 1.64 times that of noncarriers — rising to 2.02-fold for early-onset MI. The population attributable risk from this single locus was estimated at 21% for general MI and 31% for early-onset disease.

At the same time, Samani et al. 2007⁷⁷ Samani et al. 2007
Genomewide association analysis of coronary artery disease. NEJM 2007. PMID:17634449 confirmed the 9p21 region (lead SNP rs1333049, in strong LD with rs1537373) as the single strongest genetic risk locus for coronary artery disease ever identified, with a per-allele OR of 1.36 (95% CI 1.27–1.46). These findings have been replicated consistently across dozens of independent cohorts.

GWAS Catalog data specific to rs1537373 shows genome-wide significant associations with myocardial infarction (p = 2×10⁻⁷¹), brain aneurysm (p = 3×10⁻²² to 3×10⁻²⁹), coronary artery calcification (p = 4×10⁻¹¹), heart failure (p = 2×10⁻¹²), and LDL cholesterol elevation (p = 5×10⁻¹⁷).

The T2D connection at this locus was established by three concurrent 2007 GWAS that identified nearby 9p21 variants (rs10811661, rs564398) as independent T2D susceptibility signals. A meta-analysis by Cugino et al.⁸⁸ meta-analysis by Cugino et al.
Type 2 diabetes and polymorphisms on chromosome 9p21: a meta-analysis. Nutr Metab Cardiovasc Dis 2012. PMID:21315566 across 22 studies (38,455 T2D cases, 60,516 controls) confirmed per-allele OR 1.24 (P < 10⁻¹⁵) for the primary 9p21 T2D signal, with 15% population attributable risk in Caucasians.

Practical Actions

The GWAS catalog T-allele associations for rs1537373 cover both acute cardiovascular events (MI, aneurysm) and metabolic disease (T2D, LDL). Actions at this locus target:

• Reducing atherosclerotic plaque progression through dietary and monitoring strategies
• Catching asymptomatic coronary artery disease early, when intervention is most effective
• Managing the metabolic stressors that exhaust beta-cell reserves

A critical finding: Do et al. 2012⁹⁹ Do et al. 2012
INTERHEART and FINRISK study of diet-gene interaction at 9p21. PMID:22022235 showed that among those with the highest "prudent diet" scores (rich in raw vegetables and fruits), the 9p21 genetic risk for MI was effectively abolished. Among those with low prudent diet scores and two risk alleles, MI risk was doubled. The dietary interaction at this locus is one of the strongest gene-diet interactions in cardiovascular genetics.

Interactions

rs1537373 is in strong linkage disequilibrium with the primary CAD variant rs1333049 and with the T2D variants rs10811661 and rs564398 — all within the same ~200 kb stretch of 9p21.3. These variants together capture overlapping but distinct regulatory signals within the ANRIL locus. Carrying risk alleles at multiple 9p21 positions compounds risk across cardiovascular and metabolic phenotypes through shared cellular senescence biology.

The longevity-associated rs2811712 within ANRIL (covered in the Longevity & Aging category) represents a further independent signal at the same gene, primarily associated with age-related physical function and frailty — illustrating how different ANRIL isoforms modulate distinct tissue-specific aspects of aging.