Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians: a candidate gene study of the Framingham Offspring Cohort

Abstract

Valvular and vascular calcification are important early aging phenotypes and represent risk factors for cardiovascular morbidity and mortality. Klotho is a gene primarily expressed in the kidney that has an important role in calcium-phosphate homeostasis. The functional KL-VS variant of Klotho has been associated with aging and cardiovascular disease in human studies, but its role in valvular and vascular calcification remains unknown. We performed a candidate gene study in the Framingham Offspring Cohort to evaluate the effect of KL-VS variant of the Klotho gene on valvular calcification. We analyzed the Klotho KL-VS genotype (rs9536314) from the Affymetrix 550K genome-wide dataset, distributed by dbGAP, on 1389 cases and 2139 controls from the Framingham Heart Study Offspring Cohort. Allele and genotype frequencies were compared between cases and controls. Valvular calcification was defined as presence of calcification on the mitral annulus or the aortic valve as determined by echocardiography. A sensitivity analysis of coronary artery calcification by electron beam computed tomography was performed on 1363 patients. The frequency of the TT versus the TG allele was not different between the cases and the controls (39 versus 41%). The KL-VS variant of Klotho was not associated with valvular or vascular calcification, despite adequate power to detect association (86% for odds ratios ≥1.2). In sensitivity analyses, no association (P > 0.001) between other common variants of Klotho, β-Klotho or fibroblast growth factor-23 and the end points of valvular or vascular calcification was observed. In our adequately powered candidate gene study, we did not observe an association with the functional KL-VS variant of Klotho and presence of valvular or vascular calcification. Future studies aimed at combining cohorts with echocardiographic phenotypes need to be conducted to identify genetic variants associated with valvular calcification.