rs1333040 — CDKN2B-AS1

9p21 locus variant in the ANRIL long non-coding RNA gene associated with intracranial aneurysm and coronary artery disease, with the T allele increasing arterial disease risk across multiple vascular beds

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The 9p21 Chromosome Region — Shared Genetic Risk Across Your Arteries

The chromosome 9p21.3 region is one of the most studied genetic risk loci in human disease, harboring the long non-coding RNA gene CDKN2B-AS111 long non-coding RNA gene CDKN2B-AS1
Also called ANRIL — antisense noncoding RNA in the INK4 locus. rs1333040 is an intronic variant within this gene that has been independently associated with two major forms of arterial disease: coronary artery disease (CAD) and intracranial aneurysm (IA). The fact that a single locus influences vascular disease across different arterial beds — coronary arteries in the heart and cerebral arteries in the brain — suggests a shared biological mechanism affecting arterial wall integrity and cell proliferation throughout the vascular system.

The Mechanism

CDKN2B-AS1 (ANRIL) is a regulatory RNA that controls expression of neighboring genes22 controls expression of neighboring genes, including the cell cycle inhibitors CDKN2A (p16) and CDKN2B (p15). The rs1333040-T risk allele is associated with altered ANRIL expression — Cunnington et al. found that 9p21 risk SNPs correlate with up to 2-fold changes in ANRIL transcript levels. This disrupts the normal regulation of vascular smooth muscle cell proliferation and arterial wall remodeling. The rs1333040-T risk allele appears particularly relevant to intracranial aneurysm pathophysiology33 intracranial aneurysm pathophysiology.

The Evidence

The strongest evidence for rs1333040 comes from intracranial aneurysm genetics. Hashikata et al. 201044 Hashikata et al. 2010
Stroke 2010; 96 familial IA subjects and 419 sporadic IA cases vs 408 controls confirmed that the T allele is associated with both familial IA (transmission disequilibrium test, p=0.002) and sporadic IA (OR 1.28; 95% CI 1.04–1.57). A larger analysis by Nakaoka et al. 201055 Nakaoka et al. 2010
Stroke 2010, Japanese population reported a per-allele OR of 1.43 (95% CI 1.24–1.66), with stronger effects at posterior communicating artery aneurysm sites (OR 1.69). A landmark meta-analysis of over 116,000 individuals66 meta-analysis of over 116,000 individuals
Alg et al. Neurology 2013; 32,887 IA cases and 83,683 controls across 61 studies confirmed rs1333040 with a pooled OR of 1.24 (95% CI 1.20–1.29), among the most robustly replicated IA associations in the literature.

For coronary artery disease, multiple meta-analyses confirm the rs1333040 association. Hu et al. 201977 Hu et al. 2019
Bioscience Reports; meta-analysis of 15 studies on ANRIL polymorphisms and CAD found significant associations under dominant, recessive, and allelic models (all p<0.0001). Additionally, Fracassi et al. 201988 Fracassi et al. 2019
Eur Heart J Acute Cardiovasc Care; 133 STEMI patients found that TT homozygotes had significantly higher rates of coronary microvascular obstruction after myocardial infarction (p=0.03–0.04), a complication linked to worse outcomes.

Smoking substantially amplifies the 9p21 risk. Deka et al. 201099 Deka et al. 2010
Stroke; familial IA cohort demonstrated a multiplicative relationship between rs1333040 risk alleles and smoking for intracranial aneurysm risk — carriers who smoke face compounded vascular risk beyond either factor alone.

Practical Actions

The T allele at rs1333040 increases arterial disease risk through mechanisms related to vascular wall integrity and smooth muscle cell regulation. For TT homozygotes, the priority is protecting arterial health from all angles: controlling blood pressure is particularly critical because hypertension is the most potent modifiable risk factor for intracranial aneurysm rupture, and blood pressure control also directly reduces CAD events. Smoking cessation is urgent.

A family history of intracranial aneurysm in first-degree relatives, combined with TT genotype, warrants discussion with a neurologist about screening brain imaging.

Interactions

rs1333040 is in partial linkage disequilibrium with other 9p21 variants including rs1333049 and rs4977574 and rs10757278. These variants tag partly distinct functional effects within ANRIL and may compound each other's influence. Carriers of risk alleles at multiple 9p21 variants face cumulative arterial risk across the vascular system.

Genotype Interpretations

What each possible genotype means for this variant.

CC Low Vascular Risk Normal

Typical arterial disease risk at the rs1333040 locus

You carry two copies of the C reference allele at rs1333040, which is associated with typical (non-elevated) genetic risk for intracranial aneurysm and coronary artery disease from this specific variant. About 17% of people share this CC genotype globally. This is considered the lower-risk configuration at this position — standard cardiovascular risk factors such as blood pressure, cholesterol, smoking, and family history remain important for your overall arterial health.

CT Intermediate Vascular Risk Intermediate

Moderately elevated arterial disease risk from one T allele

A single T allele at rs1333040 has been associated with increased risk of intracranial aneurysm (per-allele OR approximately 1.24-1.43 in large studies) and coronary artery disease. The additive inheritance pattern means one copy confers proportionally less risk than two copies. The T allele alters ANRIL expression, which in turn influences vascular wall biology — but with one protective C allele, the regulatory disruption is partial. Key modifiable factors that interact with this locus include smoking (which multiplicatively amplifies vascular risk) and blood pressure control, which is the primary modifiable risk factor for aneurysm rupture if one does form.

TT Higher Vascular Risk High Risk

Elevated arterial disease risk from two T alleles

The TT genotype at rs1333040 represents the highest-risk configuration from this variant. The two T alleles produce greater disruption of ANRIL regulatory function compared to one copy, shifting vascular smooth muscle cell proliferation and arterial wall remodeling in a direction that promotes both atherosclerosis and focal arterial wall weakening. Large meta-analyses (e.g., Alg et al. 2013, over 116,000 individuals) confirm rs1333040 as one of the most robustly replicated intracranial aneurysm genetic associations, with a pooled OR of 1.24 per allele. TT homozygotes also appear at higher risk for coronary microvascular obstruction — the failure of blood flow restoration at the tissue level after a heart attack — which is associated with worse cardiac outcomes.

The 9p21 locus shows important gene-environment interactions. Smoking compounds arterial risk multiplicatively for T allele carriers, and the T allele's influence on arterial biology likely also interacts with hypertension — uncontrolled blood pressure is the primary driver of aneurysm growth and rupture. If you have a first-degree relative with intracranial aneurysm, your combined familial + genetic risk may warrant imaging surveillance.