rs1333049 — CDKN2B-AS1 9p21

The 9p21 Locus — Your Heart's Most Important Genetic Signal

The 9p21 region on chromosome 9 harbors the most robust and consistently replicated genetic association with coronary artery disease¹¹ genetic association with coronary artery disease
Identified in multiple genome-wide association studies in 2007, including the Wellcome Trust Case Control Consortium study ever discovered. This common variant lies within the long non-coding RNA gene CDKN2B-AS1 (also called ANRIL), positioned near cell cycle regulatory genes CDKN2A and CDKN2B. The C allele at rs1333049 is present in roughly 50% of people of European, Asian, and South Asian descent²² 50% of people of European, Asian, and South Asian descent
gnomAD population data shows allele frequencies of 0.46-0.50 in most populations, but only 26% of those of African descent, making this one of the most prevalent cardiovascular risk variants worldwide.

The Mechanism

The rs1333049 variant sits within a regulatory region that affects expression of nearby genes³³ regulatory region that affects expression of nearby genes
Located in 3'UTR of CDKN2B-AS1 long non-coding RNA involved in cell cycle control and vascular smooth muscle cell proliferation. The C risk allele appears to alter the dynamics of vascular smooth muscle cell growth, leading to accelerated atherosclerotic plaque formation⁴⁴ accelerated atherosclerotic plaque formation
Studies show C allele carriers have increased plaque burden and progression. The risk variant may work through epigenetic mechanisms⁵⁵ epigenetic mechanisms
CDKN2B-AS1 recruits polycomb repressive complexes PRC1 and PRC2 to silence nearby genes, affecting the expression of CDKN2A (p16) and CDKN2B (p15) proteins that normally regulate vascular cell growth and inflammation.

Critically, the 9p21 effect on CAD is independent of traditional cardiovascular risk factors⁶⁶ the 9p21 effect on CAD is independent of traditional cardiovascular risk factors
Association persists after adjusting for blood pressure, cholesterol, smoking, diabetes like high cholesterol, hypertension, smoking, and diabetes. This means the genetic risk adds to — rather than explains — these conventional risks. The C allele is also associated with earlier age of disease onset⁷⁷ earlier age of disease onset
CC genotype carriers develop coronary disease 2-5 years earlier than GG carriers, higher cholesterol and triglyceride levels, and increased risk of carotid atherosclerosis and peripheral artery disease.

The Evidence

The association between rs1333049 and coronary disease is among the strongest in all of human genetics⁸⁸ strongest in all of human genetics
Original GWAS reported odds ratios of 1.47 for heterozygotes and 1.9 for CC homozygotes. A 2020 meta-analysis of 50 case-control studies⁹⁹ 2020 meta-analysis of 50 case-control studies
Including 35,915 cases and 48,873 controls across diverse populations encompassing over 84,000 individuals confirmed the C allele increases coronary heart disease risk with an overall odds ratio of 1.13 (allelic comparison) and 1.29 for CC homozygotes compared to GG. In absolute terms, CC carriers have roughly 25-50% increased risk¹⁰¹⁰ CC carriers have roughly 25-50% increased risk
Risk varies by study population and specific cardiovascular outcome measured of developing coronary artery disease compared to GG carriers.

The variant affects not only disease susceptibility but also outcomes after cardiac events. The GRACE Genetics Study¹¹¹¹ GRACE Genetics Study
3,247 patients with acute coronary syndrome followed for 6 months showed that C allele carriers had significantly higher rates of recurrent myocardial infarction (hazard ratio 1.48) and cardiac death within 6 months after an acute coronary syndrome. Interestingly, one study found CC homozygotes had lower recurrence rates¹²¹² one study found CC homozygotes had lower recurrence rates
In the contemporary PCI era with optimal medical therapy when treated with modern percutaneous coronary intervention, suggesting intensive treatment may mitigate some genetic risk.

Notably, while the 9p21 variant increases risk of atherosclerotic disease development, it does not appear to affect disease progression or mortality once coronary disease is established¹³¹³ it does not appear to affect disease progression or mortality once coronary disease is established
No association found with all-cause mortality in CAD patients. This suggests the variant's primary effect is on disease initiation rather than progression.

Practical Implications

The remarkable finding about 9p21 is that genetic risk can be modified by diet¹⁴¹⁴ genetic risk can be modified by diet
INTERHEART study showed prudent diet eliminates genetic risk. In the INTERHEART study of over 8,000 individuals, those with the highest "prudent diet" scores (rich in raw vegetables and fruits) showed no increased MI risk from 9p21 variants, while those with low prudent diet scores and two risk alleles had a 2-fold increase in MI risk. A subsequent study found the Mediterranean dietary pattern reduces genetic risk¹⁵¹⁵ Mediterranean dietary pattern reduces genetic risk
Chinese cohort showed healthy diet decreased CC genotype MI risk from HR 6.39 to 2.38 for myocardial infarction in rs1333049 CC carriers.

Conversely, sugar-sweetened beverage consumption amplifies genetic risk¹⁶¹⁶ sugar-sweetened beverage consumption amplifies genetic risk
Those with highest SSB intake and CC genotype had OR 1.45 for MI, with those consuming the most sugar-sweetened beverages and carrying two C alleles showing 45% increased MI risk. This gene-environment interaction is particularly strong in populations of South Asian ancestry.

Standard cardiovascular prevention strategies apply but may be especially important for C allele carriers. This includes maintaining optimal blood pressure, cholesterol, and blood sugar¹⁷¹⁷ maintaining optimal blood pressure, cholesterol, and blood sugar
CC carriers in one study had higher total cholesterol and triglycerides, regular physical activity, smoking cessation, and stress management. Given the established risk, C allele carriers may benefit from earlier and more aggressive cardiovascular screening, including assessment of coronary artery calcium scores in middle age.

Interactions

The rs1333049 variant at 9p21 is in strong linkage disequilibrium with other 9p21 variants¹⁸¹⁸ strong linkage disequilibrium with other 9p21 variants
Including rs10757278, rs4977574, and rs10757274, meaning these variants are typically inherited together and contribute to the same biological effect. Other genetic variants affecting lipid metabolism, blood pressure regulation, and inflammation may compound with 9p21 to increase overall cardiovascular risk, though these would be assessed through comprehensive genetic panels rather than single-gene effects.

The most important interaction is with lifestyle factors. The protective effect of a diet high in fruits, vegetables, and whole grains appears to operate through anti-inflammatory and antioxidant mechanisms that may counteract the pro-atherosclerotic effects of the 9p21 risk allele. Conversely, pro-inflammatory dietary patterns (high in processed foods, sugar, and saturated fats) may amplify genetic risk.