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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Fallin, Daniele Moy, Taryn F. Yanek, Lisa R. Becker, Lewis C. Dietz, Harry C. Becker, Diane M. Judge, Daniel P. Arking, Dan E. |
| Description | Country affiliation: United States Author Affiliation: Arking DE ( McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.) |
| Abstract | 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. |
| ISSN | 00029297 |
| e-ISSN | 15376605 |
| Journal | The American Journal of Human Genetics |
| Issue Number | 5 |
| Volume Number | 72 |
| Language | English |
| Publisher | Cell Press (on behalf of American Society of Human Genetics) |
| Publisher Date | 2003-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Alleles Coronary Artery Disease Genetics Membrane Proteins Age Of Onset Diagnosis Coronary Vessels Cross-sectional Studies Electrocardiography Genetic Predisposition To Disease Genetic Testing Glucuronidase Logistic Models Radionuclide Imaging Risk Assessment Risk Factors Thallium Radioisotopes Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, P.h.s. Discipline Human Genetics |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Genetics (clinical) |
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