TY - JOUR
T1 - KLOTHO allele status and the risk of early-onset occult coronary artery disease
AU - Arking, Dan E.
AU - Becker, Diane M.
AU - Yanek, Lisa R.
AU - Fallin, Daniele
AU - Judge, Daniel P.
AU - Moy, Taryn F.
AU - Becker, Lewis C.
AU - Dietz, Harry C.
N1 - Funding Information:
This research was supported by the Howard Hughes Medical Institute (H.C.D.), the Smilow Family Foundation (H.C.D.), The Broccoli Foundation (H.C.D.), and National Institutes of Health grants AR41135 (to H.C.D. and D.E.A.), NR0224 and HL49762 (to D.M.B, L.R.Y., T.F.M., and L.C.B.), and M01 RR00052 (to Johns Hopkins University School of Medicine General Clinical Research Center, supporting D.M.B, L.R.Y., T.F.M., and L.C.B).
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
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U2 - 10.1086/375035
DO - 10.1086/375035
M3 - Article
C2 - 12669274
AN - SCOPUS:0038744264
SN - 0002-9297
VL - 72
SP - 1154
EP - 1161
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -