rs9536314

mixedMag 5.5

This is a variant in the KL gene that changes a phenylalanine to an valine.

Key Literature Trait Associations

Longevity and Cognitive Function

The rs9536314 variant in the KL (Klotho) gene defines the KL-VS haplotype (F352V). Heterozygosity for the KL-VS haplotype, found in ~20–25% of the general population, is associated with higher circulating klotho protein levels, improved cognitive performance, greater cortical brain volume, and potentially longer lifespan. Klotho is an anti-aging protein modulating insulin signaling and FGF pathways. Importantly, benefits appear specific to heterozygous carriers — homozygous carriers do not show the same advantages.

Arking DE et al. “Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity.” Circulation Research (2005)

Allele G

OR 1.57

p 2.0e-4

N 525

Preliminary work

Ashkenazi Jewish

Yokoyama JS et al. “Variation in longevity gene KLOTHO is associated with greater cortical volumes.” Annals of Clinical and Translational Neurology 2(3):215-230 (2015)

Allele G

OR 1.20

p 1.0e-2

Candidate gene study

Belloy ME et al. “KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers.” Neurobiology of Aging (2021)

Allele G

OR 0.67

p 3.5e-3

N 3,581

Preliminary work

European

Almeida OP et al. “Longevity Klotho gene polymorphism and the risk of dementia in older men.” Maturitas (2017)

Allele G

OR —

p 1.1e-2

N 527

Preliminary work

European

Driscoll IF et al. “KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.” Alzheimer's & Dementia : the Journal of the Alzheimer's Association (2024)

Allele G

OR —

p —

N 454

Candidate gene study

European

Zhu Z et al. “Klotho gene polymorphisms are associated with healthy aging and longevity: Evidence from a meta-analysis.” Mechanisms of Ageing and Development (2019)

Allele G

OR —

p —

Meta-analysis

multi-ancestry

Arking DE et al. “Association of human aging with a functional variant of klotho.” Proceedings of the National Academy of Sciences of the United States of America (2002)

Allele G

OR 2.59

p 2.3e-3

Candidate gene study

multi-ancestry

Coronary artery disease

The KL-VS allele (containing the rs9536314 G allele / V352 form) was independently associated with a ~1.9-fold increased risk for subclinical (occult) coronary artery disease in apparently healthy siblings of early-onset CAD patients across two independent high-risk cohorts. The risk was modified by HDL cholesterol and smoking status, with elevated HDL attenuating and current smoking amplifying the effect. This finding is from a candidate-gene era study and has not been formally replicated in large GWAS.

Arking DE et al. “KLOTHO allele status and the risk of early-onset occult coronary artery disease.” American Journal of Human Genetics (2003)

Allele G

OR 1.90

p 5.0e-3

N 956

Preliminary work

European

Stroke

KL-VS heterozygotes (one copy of rs9536314 T/F352 allele) showed significantly lower stroke risk compared to non-carriers in a centenarian cohort, while KL-VS homozygotes showed dramatically elevated stroke risk (OR≈30). This non-linear pattern mirrors the heterozygous advantage seen for longevity. The study was small (n=525 Ashkenazi Jews) and the finding has not been replicated in a large GWAS, so caution is warranted.

Arking DE et al. “Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity.” Circulation Research (2005)

Allele T

OR 0.17

p 5.0e-2

N 525

Preliminary work

Ashkenazi Jewish

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ClinVar annotation

Benign★★★☆

6 submitters9 publications

KLOTHO POLYMORPHISM; Tumoral calcinosis, hyperphosphatemic, familial, 3

View on ClinVar →

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Research that mentions this SNP (1)

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Variation in longevity gene KLOTHO is associated with greater cortical volumes.

AssociationN=414Yokoyama JS et al.(2015)· Annals of clinical and translational neurology

In two independent cohorts of cognitively normal older adults (n=414), the KL-VS haplotype in KLOTHO was associated with greater right dorsolateral prefrontal cortex (rDLPFC) volume (P=2.64×10⁻⁵ in meta-analysis) and better executive function (P=4.71×10⁻⁴), with KL-VS heterozygotes showing superior baseline cognitive performance. The effect of KL-VS on executive function was partially mediated by rDLPFC volume (~12%), suggesting the longevity-associated variant influences brain structure and cognitive resilience in aging.

Traits studied:Brain gray matter volume (right dorsolateral prefrontal cortex)Executive functionProcessing speedWorking memory

rs9536314

Key Literature Trait Associations

Longevity and Cognitive Function

Coronary artery disease

Stroke

ClinVar annotation

Research that mentions this SNP (1)

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