Authors: Arking DE; Atzmon G; Arking A; Barzilai N; Dietz HC
Abstract: 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 > or =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 > or =79; P<0.01), a heterozygous advantage for longevity was observed for individuals > or =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.
Keywords: Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Blood Pressure/*genetics; Cardiovascular Diseases/epidemiology; Cholesterol, HDL/*blood; Cross-Sectional Studies; Czech Republic/epidemiology; Europe, Eastern/ethnology; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Jews/genetics; Longevity/*genetics; Male; Middle Aged; Models, Genetic; Multivariate Analysis; Mutation, Missense; Odds Ratio; Proportional Hazards Models; Prospective Studies; Risk Factors; Selection, Genetic; Stroke/*genetics; Survival Analysis|
Journal: Circulation research Volume: 96 Issue: 4 Pages: 412-8 Date: Jan. 29, 2005 PMID: 15677572 |
Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circulation research 96: 412-8.
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