Published Online
on March 19, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on November 6, 2006
Revised on November 29, 2006

CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

Chin B. Eap; Murielle Bochud; Robert C. Elston; Pascal Bovet; Marc P. Maillard; Juerg Nussberger; Laurent Schild; Conrad Shamlaye; and Michel Burnier^*

From the Unité de Biochimie et Psychopharmacologie Clinique (C.B.E.), Centre des Neurosciences Psychiatriques, Département de Psychiatrie-Centre Hospitalier Universitaire Vaudois, Prilly, Switzerland; Institut Universitaire de Médecine Sociale et Préventive (M.B., P.B.), Lausanne, Switzerland; the Department of Epidemiology and Biostatistics (M.B., R.C.E.), Case Western Reserve University, Cleveland, Ohio; Ministry of Health (P.B., C.S.), Seychelles; Service de Néphrologie (M.P.M., M.B.), and Service d’Angiologie (J.N.), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and the Département de Pharmacologie et Toxicologie (L.S.), Université de Lausanne, Lausanne, Switzerland.

^* To whom correspondence should be addressed. E-mail: michel.burnier{at}chuv.ch.

Abstract--The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.

Key words: blood pressure • genes • sodium • renin-angiotensin system • P glycoprotein

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