Published online before print January 27, 2005, doi: 10.1161/01.RES.0000157171.04054.30
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Submitted on August 17, 2004
Revised on January 7, 2005
Accepted on January 14, 2005
Association Between the Functional Variant of KLOTHO Allele and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity
Dan E. Arking ;
From the McKusick-Nathans Institute of Genetic Medicine (D.E.A., H.C.D.), Johns Hopkins University School of Medicine, Baltimore, Md; Institute for Aging Research (G.A., N.B.), Albert Einstein College of Medicine, Bronx, NY; Johns Hopkins University (A.A.), Baltimore, Md; and Howard Hughes Medical Institute (H.C.D.).
* To whom correspondence should be addressed. E-mail: hdietz{at}jhmi.edu.
We identified previously a functional variant of KLOTHO, termed KL-VS, that is associated with human aging and early-onset occult coronary artery disease. Here, we determine whether the KL-VS allele influences cardiovascular disease risk factors, cardiovascular events, and ultimately, mortality. A total of 525 Ashkenazi Jews composed of 216 probands (age 
95 years) and 309 unrelated individuals (ages 51 to 94) were genotyped for the KL-VS allele. In concordance with our previous data in Czech individuals (age 79; P<0.01), a heterozygous advantage for longevity was observed for individuals 79 years of age (P<0.004). Combined analysis indicates a 1.57-fold (95% CI, 1.23 to 1.98) increased odds ratio (OR) for 5-year survival in two independent populations (P<0.0002). Cardiovascular disease risk factors was assessed through multivariate regression analysis, demonstrating that high-density lipoprotein cholesterol (HDL-C; P<0.05) and systolic blood pressure (SBP; P<0.008) are associated with KL-VS genotype. History of vascular events was analyzed using logistic regression, indicating that after adjustment for traditional risk factors, heterozygous individuals were at significantly lower risk for stroke than wild-type individuals (OR, 5.88; 95% CI, 1.18 to 29.41), whereas homozygous KL-VS individuals had the highest risk (OR, 30.65; 95% CI, 2.55 to 368.00). Similarly, prospective analysis of mortality in probands using Cox regression indicates that wild-type individuals have a 2.15-fold (95% CI, 1.18 to 3.91) and homozygous KL-VS individuals a 4.49-fold (95% CI, 1.35 to 14.97) increase in relative risk for mortality after adjusting for potential confounders. Thus, cross-sectional and prospective studies confirm a genetic model in which the KL-VS allele confers a heterozygous advantage in conjunction with a marked homozygous disadvantage for HDL-C levels, SBP, stroke, and longevity.
Key words: aging • cardiovascular genomics • genetics • lipids • hypertension
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