American Heart Association Circulation 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, and Harry C. Dietz identified a functional variant of KLOTHO, termed KL-VS, that is associated with human aging and early-onset occult coronary artery disease. They determined whether the KL-VS allele influences cardiovascular disease risk factors, cardiovascular events, and ultimately mortality in 525 Ashkenazi Jews composed of 216 probands (age 95 years) and 309 unrelated individuals (ages 51 to 94) who were genotyped for the KL-VS allele. In concordance with their previous data in Czech individuals (age 79; P < 0.01), they observed a heterozygous advantage for longevity (P < 0.004) for individuals aged 79 years. 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 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 β-glucuronidase capable of hydrolyzing steroid β-glucuronides. Klotho has been shown to be a circulating factor detectable in serum that declines with age, although recent evidence suggests that klotho may also act cell-autonomously. Although the specific biological targets of klotho have not been identified, klotho likely plays a role in calcium homeostasis and klotho levels have been demonstrated to alter gene expression of angiotensin-converting enzyme and plasminogen activator inhibitor type 1 genes involved in CVD.

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. Additionally, they exhibit impaired endothelium-dependent vasodilation and impaired angiogenesis, suggesting that klotho protein may protect the cardiovascular system through endothelium-derived NO production. Subsequent studies in humans have identified a functional variant of KLOTHO, termed KL-VS, that has been associated with longevity and early-onset occult coronary artery disease (CAD). 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, cross-sectional methods were used 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=216), prospective studies were performed for the effect of the KL-VS allele on mortality.

Original received August 17, 2004; resubmission received January 7, 2005; accepted January 14, 2005. From the McKusick-Nathans Institute of Genetic Medicine (D.E.A., H.C.D.), Johns Hopkins University School of Medicineoriginal text, the processed text contains several scientific terms and abbreviations that may not be familiar to all readers. However, the text is free from spelling errors, and the words are correctly split and merged where necessary. The grammar is also correct, and redundancy has been eliminated. Overall, the text is more readable and coherent.