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(Hypertension. 2004;44:156.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Genetic Variation in CYP11B2 and AT1R Influences Heart Rate Variability Conditional on Sodium Excretion

Katarzyna Stolarz; Jan A. Staessen; Kalina Kawecka-Jaszcz; Eva Brand; Giuseppe Bianchi; Tatiana Kuznetsova; Valérie Tikhonoff; Lutgard Thijs; Thomas Reineke; Speranta Babeanu; Edoardo Casiglia; Robert Fagard; Jan Filipovsk; Jan Peleka; Yuri Nikitin; Harry Struijker-Boudier; Tomasz Grodzicki on behalf of the European Project On Genes in Hypertension (EPOGH) Investigators

From the Study Coordinating Centre (K.S., J.A.S., T.K., L.T., R.F.), Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Belgium; First Cardiac Department (K.S., K.K.-J.) and Department of Internal Medicine and Gerontology (T.G.), Jagiellonian University, Kraków, Poland; University Medical Center Charité, Department of Internal Medicine (E.B., T.R.), Division of Endocrinology and Nephrology, Campus Benjamin Franklin, Berlin, Germany; Cattedra e Scuola di Nefrologia (G.B.), Universitá Vita e Salute San Raffaele, Milano, Italy; Institute of Internal Medicine (T.K., Y.N.), Novosibirsk, Russian Federation; Department of Clinical and Experimental Medicine (V.T., E.C.), University of Padova, Italy; San Luca Hospital (S.B.), Bucharest, Romania; Department of Internal Medicine II (J.F.), Charles University Medical School, Pilsen, Czech Republic; General Faculty Hospital (J.P.), Prague, Czech Republic; Department of Pharmacology and Toxicology (H.S.-B.), Cardiovascular Research Institute, Maastricht University, The Netherlands.

Correspondence to Jan A. Staessen, MD PhD, 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

Sympathetic tone increases with stimulation of the renin-angiotensin system and is under the influence of salt intake. In the European Project On Genes in Hypertension (EPOGH), we investigated whether polymorphisms in the genes encoding aldosterone synthase (CYP11B2 C–344T) and the type-1 angiotensin II receptor (AT1R A1166C) affect the autonomic modulation of heart rate at varying levels of salt intake. We measured the low frequency (LF) and high frequency (HF) components of heart rate variability and their ratio (LF:HF) in the supine and standing positions in 1797 participants (401 families and 320 unrelated subjects) randomly selected from 6 European populations, whose average urinary sodium excretion ranged from 163 to 245 mmol/d. In multivariate analyses with sodium excretion analyzed as a continuous variable, we explored the phenotype–genotype associations using generalized estimating equations and quantitative transmission disequilibrium tests. Across populations, there was no heterogeneity in the phenotype–genotype relations. The genotypic effects differed according to sodium excretion. In subjects with sodium excretion <190 mmol/d (median), supine heart rate, LF, and LF:HF increased and HF decreased with the number of CYP11B2 –344T alleles, and the orthostatic changes in LF, HF, and LF:HF were blunted in carriers of the AT1R 1166C allele. In subjects with sodium excretion >190 mmol/d, these associations with the CYP11B2 and AT1R polymorphisms were nonsignificant or in the opposite direction, respectively. Thus, CYP11B2 C–344T and AT1R A1166C polymorphisms affect the autonomic modulation of heart rate, but these genetic effects depend on sodium excretion.

Key Words: aldosterone • receptors, angiotensin • genetics • heart rate • sodium

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