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(Circulation. 2004;110:2644-2650.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Left Ventricular Mass in Relation to Genetic Variation in Angiotensin II Receptors, Renin System Genes, and Sodium Excretion

Tatiana Kuznetsova, MD, PhD; Jan A. Staessen, MD, PhD; Lutgarde Thijs, MSc; Christiane Kunath, MD; Agnieszka Olszanecka, MD, PhD; Andrew Ryabikov, MD; Valérie Tikhonoff, MD; Katarzyna Stolarz, MD, PhD; Giuseppe Bianchi, MD, PhD; Edoardo Casiglia, MD, PhD; Robert Fagard, MD, PhD; Stefan-Martin Brand-Herrmann, MD, PhD; Kalina Kawecka-Jaszcz, MD, PhD; Sofia Malyutina, MD, PhD; Yuri Nikitin, MD, PhD; Eva Brand, MD, for the European Project On Genes in Hypertension (EPOGH) Investigators

From the Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium (T.K., J.A.S., L.T., R.F.); Institute of Internal Medicine, Novosibirsk, Russian Federation (T.K., A.R., S.M., Y.N.); Department of Endocrinology and Nephrology, Charité, University of Berlin, Campus Benjamin Franklin, Berlin, Germany (C.K., E.B.); First Cardiac Department, Jagiellonian University, Cracow, Poland (A.O., K.S., K.K.-J.); Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy (V.T., E.C.); Cattedra e Scuola di Nefrologia, Universita Vita e Salute San Raffaele, Milano, Italy (G.B.); Department of Molecular Genetics for Cardiovascular Disease, Institute for Arteriosclerosis Research, University of Münster, Münster, Germany (S.-M.B-H.); and Department of Internal Medicine D (Nephrology and Hypertension), University Clinic Münster, Münster, Germany (E.B.).

Correspondence to J.A. Staessen, Study Coordinating Centre, Laboratory of Hypertension, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Campus Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail jan.staessen{at}med.kuleuven.ac.be

Received December 19, 2003; de novo received April 12, 2004; revision received June 9, 2004; accepted June 10, 2004.

Background— In the European Project On Genes in Hypertension (EPOGH), we investigated in 3 populations to what extent left ventricular mass (LVM) was associated with genetic variation in the angiotensin II receptors type 1 (AGTR1 A1166C) and type 2 (AGTR2 G1675A) while accounting for possible gene–gene interactions with the angiotensin-converting enzyme (ACE D/I) and angiotensinogen (AGT –532C/T) polymorphisms.

Methods and Results— We randomly recruited 221 nuclear families (384 parents, 431 offspring) in Cracow (Poland), Novosibirsk (Russia), and Mirano (Italy). Echocardiographic LVM was indexed to body surface area, adjusted for covariates, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests in a population-based and family-based approach, respectively. For AGTR1 and AGTR2, there was no heterogeneity in the phenotype–genotype relations across populations. LVM index was unrelated to the AGTR1 A1166C polymorphism. In men, in the population- and family-based analyses, the allelic effects of the AGTR2 polymorphism on LVM index differed (P=0.01) according to sodium excretion. In women, this gene–environment interaction did not reach statistical significance. In untreated men, LVM index (4.2 g/m² per 100 mmol) and left ventricular internal diameter (0.73 mm/100 mmol) increased (P<0.02) with higher sodium excretion in the presence of the G allele with an opposite tendency in A allele carriers. The ACE D/I polymorphism, together with the ACE genotype-by-sodium interaction term, significantly and independently improved the models relating LVM index to the AGTR2 polymorphism and the AGTR2 genotype-by-sodium interaction.

Conclusions— The present findings support the hypothesis that in men the AGTR2 G1675A and the ACE D/I polymorphisms independently influence LVM and that salt intake modulates these genetic effects.

Key Words: angiotensin • genes • hypertrophy • sodium • receptors

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