rs1556516

mixedMag 5.5

This is a intron variant variant in the CDKN2B-AS1 gene.

Key Literature Trait Associations

Coronary Artery Disease

rs1556516 lies in the 9p21.3 locus within the long non-coding RNA CDKN2B-AS1 (ANRIL). This locus is the strongest common genetic risk factor for coronary artery disease, replicated across all major ethnic groups. The risk allele alters ANRIL splicing and expression, disrupting regulation of the adjacent tumor suppressors CDKN2A/B (p16INK4a/p15INK4b), promoting vascular smooth muscle proliferation and atherosclerotic plaque formation.

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele C

OR —

β 0.152

p 9.0e-76

N 635,969

Major Consortium StudyLarge GWAS

multi-ancestry

Samani NJ et al. “Genomewide association analysis of coronary artery disease.” The New England Journal of Medicine 357(5):443-453 (2007)

Allele C

OR 1.29

p 1.0e-20

Large GWAS

Tcheandjieu C et al. “Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.” Nature Medicine 28(8):1679-1692 (2022)

Allele C

OR —

β 0.071

p 4.0e-6

N 250,000

Small GWAS

Hispanic/Latino

Helgadottir A et al. “A common variant on chromosome 9p21 affects the risk of myocardial infarction.” Science (new York, N.y.) 316(5830):1491-1493 (2007)

Allele C

OR 1.64

p 1.0e-12

N 17,354

Large GWAS

European

Heart failure

The C allele at rs1556516 is associated with modestly elevated heart failure risk (OR≈1.06) in a large genome-wide association study of 47,309 heart failure cases and 930,014 controls. The association, identified by Shah et al. (2020, Nature Communications), reached genome-wide significance (p=2×10⁻¹⁵) and implicates the 9p21 CDKN2B-AS1 locus in heart failure pathogenesis, consistent with its broader role in cardiovascular disease. The modest OR reflects the polygenic nature of heart failure risk.

Shah S et al. “Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.” Nature Communications 11(1):163 (2020)

Allele C

OR 1.06

p 2.0e-15

N 977,323

Large GWAS

European

Vestibular schwannoma

The C allele at rs1556516 is paradoxically associated with reduced risk of sporadic vestibular schwannoma (OR=0.67, p=1.47×10⁻¹³), as identified by Sadler et al. (2023, Brain) in 911 cases and 5,500 controls. This protective direction is unusual compared to the allele's cardiovascular risk profile and likely reflects the complex tumor-suppressor biology of the 9p21 INK4 locus (CDKN2A/CDKN2B), where different haplotype configurations may have opposing effects on benign nerve sheath tumorigenesis versus cardiovascular disease.

Sadler KV et al. “Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.” Brain : a Journal of Neurology (2023)

Allele C

OR 0.67

p 1.5e-13

N 6,411

Large GWAS

European

Parental lifespan

The G allele at rs1556516 is consistently associated with longer parental lifespan across very large UK Biobank analyses, with the C allele correspondingly linked to shorter survival. Pilling et al. (2017) identified this locus among 25 associated with longevity in 389,166 participants, and Timmers et al. (2019) confirmed the association in over 1 million parental lifespans, estimating approximately 0.25 additional years of parental life per G allele. The effect is largely mediated through the locus's cardiovascular risk reduction, as CDKN2B-AS1 variants influencing CAD and MI are major determinants of lifespan at the population level.

Timmers PR et al. “Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.” Elife 8 (2019)

Allele C

OR —

β 0.251

p 7.0e-11

N 1,000,000

Large GWAS

European

Pilling LC et al. “Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.” Aging 9(12):2504-2520 (2017)

Allele C

OR —

β 0.018

p 5.0e-16

N 389,166

Major Consortium StudyLarge GWAS

European

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GWAS Catalog Trait Associations (3)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

rs1556516

Key Literature Trait Associations

Coronary Artery Disease

Heart failure

Vestibular schwannoma

Parental lifespan

GWAS Catalog Trait Associations (3)

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