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(Circulation Research. 2005;97:1360.)
© 2005 American Heart Association, Inc.

Clinical Research

Protective Effect of the KCNMB1 E65K Genetic Polymorphism Against Diastolic Hypertension in Aging Women and Its Relevance to Cardiovascular Risk

Mariano Sentí^*, José M. Fernández-Fernández^*, Marta Tomás, Esther Vázquez, Roberto Elosua, Jaume Marrugat, Miguel A. Valverde

From the Unitat de Lípids i Epidemiologia Cardiovascular (M.S., M.T., R.E., J.M.), Institut Municipal d’Investigació Mèdica, Barcelona, Spain; Grup de Canalopaties (M.S., J.M.F.-F., E.V., M.A.V.), Unitat de Senyalització Cel·lular, Universitat Pompeu Fabra, Barcelona, Spain; and Universitat Autònoma de Barcelona (J.M.), Barcelona, Spain.

Correspondence to Dr Mariano Sentí, Unitat de Lípids i Epidemiologia Cardiovascular, Institut Municipal d’Investigació Mèdica (IMIM), C/ Dr Aiguader 80, Barcelona 08003, Spain. E-mail msenti{at}imim.es

The E65K polymorphism in the ß₁-subunit of the large-conductance, Ca²⁺-dependent K⁺ (BK) channel, a key element in the control of arterial tone, has recently been associated with low prevalence of diastolic hypertension. We now report the modulatory effect of sex and age on the association of the E65K polymorphism with low prevalence of diastolic hypertension and the protective role of E65K polymorphism against cardiovascular disease. We analyzed the genotype frequency of the E65K polymorphism in 3924 participants selected randomly in two cross-sectional studies. A five-year follow-up of the cohort was performed to determine whether cardiovascular events had occurred since inclusion. Estrogen modulation of wild-type and mutant ion channel activity was assessed after heterologous expression and electrophysiological studies. Multivariate regression analyses showed that increasing age upmodulates the protective effect of the K allele against moderate-to-severe diastolic hypertension in the overall group of participants (odds ratio [OR], 0.35; P=0.006). The results remained significant when analyses were restricted to women (OR, 0.18; P=0.02) but not men (OR, 0.46; P=0.09). This effect was independent of the reported acute modulation of BK channels by estrogen. A five-year follow-up study also demonstrated a reduced age- and sex-adjusted hazard ratio of 0.11, 95% CI, 0.01 to 0.79 of K-carriers for "combined cardiovascular disease" (myocardial infarction and stroke) compared with EE homozygotes. Our study provides the first genetic evidence for the different impact of the BK channel in the control of human blood pressure in men and women, with particular relevance in aging women, and highlights the E65K polymorphism as one of the strongest genetic factors associated thus far to protection against myocardial infarction and stroke.

Key Words: BK channel • estradiol • hypertension • KCNMB1 gene • cardiovascular risk • sex • age

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