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.
Becker, Diane M.
Yanek, Lisa R.
Fallin, Daniele
Judge, Daniel P.
Moy, Taryn F.
Becker, Lewis C.
Dietz, Harry C.
Item Type: 
Journal Article
Publication Title: 
American Journal of Human Genetics
Journal Abbreviation: 
Am. J. Hum. Genet.
Publication Date: 
Publication Year: 
Library Catalog: 
NCBI Published Medical (?)
PMID: 12669274 PMCID: PMC1180268

Turabian/Chicago Citation

Dan E. Arking, Diane M. Becker, Lisa R. Yanek, Daniele Fallin, Daniel P. Judge, Taryn F. Moy, Lewis C. Becker and Harry C. Dietz. 2003-05. "KLOTHO allele status and the risk of early-onset occult coronary artery disease." American Journal of Human Genetics 72: 5: 1154-1161. 10.1086/375035.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1086/375035 | issn = 0002-9297 | volume = 72 | pages = 1154-1161 | last = Arking | first = Dan E. | coauthors = Becker, Diane M., Yanek, Lisa R., Fallin, Daniele, Judge, Daniel P., Moy, Taryn F., Becker, Lewis C., Dietz, Harry C. | title = KLOTHO allele status and the risk of early-onset occult coronary artery disease | journal = American Journal of Human Genetics | date = 2003-05 | pmid = | pmc = }} </ref>