KLOTHO allele status and the risk of early-onset occult coronary artery disease

Abstract

We previously identified a functional variant of KLOTHO (termed "KL-VS"), which harbors two amino acid substitutions in complete linkage disequilibrium and is associated with reduced human longevity when in homozygosity. Klotho-deficient mice display extensive arteriosclerosis when fed a normal diet, suggesting a potent genetic predisposition. To determine whether klotho influences atherosclerotic risk in humans, we performed cross-sectional studies to assess the association between the KL-VS allele and occult coronary artery disease (CAD) in two independent samples of apparently healthy siblings of individuals with early-onset (age <60 years) CAD (SIBS-I [N=520] and SIBS-II [N=436]). Occult CAD was defined as the occurrence of a reversible perfusion defect during exercise thallium scintigraphy and/or as an abnormal result of an exercise electrocardiogram (SIBS-I, n=97; SIBS-II, n=56). In SIBS-I, the KL-VS allele conferred a relative odds of 1.90 (95% confidence interval 1.21-2.98) for occult CAD, after adjusting for familial intraclass correlations (P<.005). Logistic regression modeling, incorporating known CAD risk factors, demonstrated that the KL-VS allele is an independent risk factor (P<.019) and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension (P<.022) and increasing high-density lipoprotein cholesterol (HDL-C) levels (P<.022) mask or reduce the risk conferred by the KL-VS allele, respectively, whereas current smoking (P<.004) increases the risk. Remarkably concordant effects of the KL-VS allele and modifying factors on the risk of occult CAD were seen in SIBS-II. These results demonstrate that the KL-VS allele is an independent risk factor for occult CAD in two independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL-C level, appear to influence the risk imposed by this allele.

Figure 1

Frequency of occult CAD in the SIBS-I sample, stratified by KLOTHO genotype. P=.002 for trend (unadjusted). Error bars indicate 95% CIs.

Figure 2

Frequency of occult CAD in the SIBS-I sample, stratified by hypertension and KLOTHO genotype. Left, Normotensive individuals. Right, Hypertensive individuals. Heterozygous and homozygous KL-VS allele carriers were combined because of the small numbers in the latter group after stratification for hypertension. Error bars indicate 95% CIs.

Figure 3

Frequency of occult CAD in the SIBS-I sample, stratified by KLOTHO genotype and current smoking status. Heterozygous and homozygous KL-VS allele carriers were combined because of the small numbers in the latter group after stratification for current smoking status. Error bars represent 95% CIs.

Figure 4

Relative odds of occult CAD conferred by the KL-VS allele with increasing HDL-C Levels. Blackened squares represent SIBS-I normotensive smokers. Closed triangles represent all SIBS-II normotensive individuals.