KLOTHO allele status and the risk of early-onset occult coronary artery disease.
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.
Arking
Dan E
DE
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Becker
Diane M
DM
Yanek
Lisa R
LR
Fallin
Daniele
D
Judge
Daniel P
DP
Moy
Taryn F
TF
Becker
Lewis C
LC
Dietz
Harry C
HC
D000328:Adult; D017668:Age of Onset; D000483:Alleles; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000235:genetics*; D003331:Coronary Vessels / Q000000981:diagnostic imaging; D003430:Cross-Sectional Studies; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005966:Glucuronidase; D006801:Humans; D000090265:Klotho Proteins; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011877:Radionuclide Imaging; D018570:Risk Assessment; D012307:Risk Factors; D035781:Siblings; D013794:Thallium Radioisotopes
D008565:Membrane Proteins; D013794:Thallium Radioisotopes; D005966:Glucuronidase; D000090265:Klotho Proteins