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(Circulation Research. 2005;96:412.)
© 2005 American Heart Association, Inc.

Clinical Research

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

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.).

Correspondence to Harry C. Dietz, Johns Hopkins University School of Medicine, 733 N Broadway, Room 539, Baltimore, MD 21205. E-mail hdietz{at}jhmi.edu

We 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 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 were 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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