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Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity Dan E. Arking, Gil Atzmon, Albert Arking, Nir Barzilai and Harry C. Dietz

Circ Res. 2005;96:412-418; originally published online January 27, 2005;

Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright © 2005 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571

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Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity

Dan E. Arking, Gil Atzmon, Albert Arking, Nir Barzilai, Harry C. Dietz

previously identified 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   D<( concordance with our previous data in Czech individuals (age 79; P 0.01), a heterozygous advantage for longevity 27 P<( was observed for individuals 79 years of age (P 0.004). Combined analysis indicates a 1.57-fold (95% CI, 1.23 to P<() 1.98) increased odds ratio (OR) for 5-year survival in two independent populations (P 0.0002). Cardiovascular disease risk factors were assessed through multivariate regression analysis, demonstrating that high-density lipoprotein P<() meeeP<() 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. (Circ Res. 2005;96:412-418.)

Key Words: aging  cardiovascular genomics  genetics  lipids  hypertension

Recent work has demonstrated that klotho is a novel  | B-s -glucuronidase capable of hydrolyzing steroid -glucuronides.6 Klotho has been shown to be a circulating factor detectable in serum that declines with age,7 although recent evidence suggests that klotho may also act cell-autonomously.8 Although the specific biological targets of klotho have not been identified, klotho likely plays a role in calcium homeostasis,9 and klotho levels have been demonstrated to alter gene expression of angiotensin-converting enzyme (MIM 106180)10 and plasmino- gen activator inhibitor type 1 (PAI-1 [MIM 173360]),11 genes involved in CVD.12,13

cardiovascular disease (CVD) was postulated initially on the basis of the observation that Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis.1 Additionally, they exhibit impaired endothelium- dependent vasodilation2 and impaired angiogenesis,3 sug- gesting that klotho protein may protect the cardiovascular system through endothelium-derived NO production. Sub- sequent studies in humans have identified a functional variant of KLOTHO, termed KL-VS, that has been associ- ated with longevity4 and early-onset occult coronary artery disease (CAD).5 This allele is common in the general   population (frequency 0.16) and harbors three mutations in the coding region, of which one is silent, and two code for missense mutations F352V and C370S, which alter klotho metabolism.

In the present population-based study of 525 Ashkenazi Jews, we used cross-sectional methods to examine the effect of the KL-VS allele on longevity, cardiovascular risk factors, and cardiovascular events. In an elderly subset of this population (age   95 years; n(cid:3) 216), we were able to perform prospective studies for the effect of the KL-VS allele on mortality.