KLOTHO allele status and the risk of early-onset occult coronary artery disease

Am J Hum Genet. 2003 May;72(5):1154-61. doi: 10.1086/375035. Epub 2003 Mar 31.


We previously identified a functional variant of KLOTHO (termed "KL-VS"), which harbors two amino acid substitutions in complete linkage disequilibrium and is associated with reduced human longevity when in homozygosity. Klotho-deficient mice display extensive arteriosclerosis when fed a normal diet, suggesting a potent genetic predisposition. To determine whether klotho influences atherosclerotic risk in humans, we performed cross-sectional studies to assess the association between the KL-VS allele and occult coronary artery disease (CAD) in two independent samples of apparently healthy siblings of individuals with early-onset (age <60 years) CAD (SIBS-I [N=520] and SIBS-II [N=436]). Occult CAD was defined as the occurrence of a reversible perfusion defect during exercise thallium scintigraphy and/or as an abnormal result of an exercise electrocardiogram (SIBS-I, n=97; SIBS-II, n=56). In SIBS-I, the KL-VS allele conferred a relative odds of 1.90 (95% confidence interval 1.21-2.98) for occult CAD, after adjusting for familial intraclass correlations (P<.005). Logistic regression modeling, incorporating known CAD risk factors, demonstrated that the KL-VS allele is an independent risk factor (P<.019) and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension (P<.022) and increasing high-density lipoprotein cholesterol (HDL-C) levels (P<.022) mask or reduce the risk conferred by the KL-VS allele, respectively, whereas current smoking (P<.004) increases the risk. Remarkably concordant effects of the KL-VS allele and modifying factors on the risk of occult CAD were seen in SIBS-II. These results demonstrate that the KL-VS allele is an independent risk factor for occult CAD in two independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL-C level, appear to influence the risk imposed by this allele.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Alleles*
  • Coronary Artery Disease / diagnosis
  • Coronary Artery Disease / genetics*
  • Coronary Vessels / diagnostic imaging
  • Cross-Sectional Studies
  • Electrocardiography
  • Exercise Test
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Glucuronidase
  • Humans
  • Klotho Proteins
  • Logistic Models
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Radionuclide Imaging
  • Risk Assessment
  • Risk Factors
  • Siblings
  • Thallium Radioisotopes


  • Membrane Proteins
  • Thallium Radioisotopes
  • Glucuronidase
  • Klotho Proteins