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(Hypertension. 2008;51:1643.)
© 2008 American Heart Association, Inc.

Original Articles

Blood Pressure and Renal Sodium Handling in Relation to Genetic Variation in the DRD1 Promoter and GRK4

Jan A. Staessen; Tatiana Kuznetsova; Haifeng Zhang; Marc Maillard; Murielle Bochud; Sandra Hasenkamp; Judith Westerkamp; Tom Richart; Lutgarde Thijs; Xinli Li; Stefan-Martin Brand-Herrmann; Michel Burnier; Eva Brand

From the Genetic Epidemiology Unit, Department of Epidemiology (J.A.S., T.R.), University of Maastricht, The Netherlands; the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (J.A.S., T.K., H.Z., T.R., L.T.), University of Leuven, Belgium; the Department of Cardiology (H.Z., X.L.), the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; the Division of Nephrology and Hypertension (M.M., M. Bochud, M. Burnier), University of Lausanne, Switzerland; the Department of Internal Medicine D (S.H., J.W., E.B.), Nephrology and Hypertension, University of Münster, Germany; and the Leibniz Institute for Arteriosclerosis Research (S.-M.B.-H.), Department of Molecular Genetics of Cardiovascular Disease, University of Münster, Germany.

Correspondence to Jan A. Staessen, Genetic Epidemiology Unit, Department of Epidemiology, Peter Debyeplein 1, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail ja.staessen{at}epid.unimaas.nl

Activation of type-1 dopamine receptors (DRD1) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE_Na) and proximal (RNa_prox) and distal (RNa_dist) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter (A–48G, G–94A, and C–800T) and GRK4 (Ala142Val). The frequent DRD1 haplotypes were AGC (48.2%), GGT (34.4%), and AAC (14.3%). While standardizing to mean sodium excretion (8.7 mmol/h) and adjusting for covariates and relatedness, RNa_dist was lower in DRD1 –94GG homozygotes than –94A allele carriers (effect size, –0.94%; P=0.005) with opposite findings for FE_Na (+0.084%; P=0.014). AGC carriers (–0.88%; P=0.012) and AAC carriers (+1.00%; P=0.004) had different RNa_dist compared to corresponding noncarriers. Furthermore, FE_Na was lower in AAC carriers than in noncarriers (–0.082%; P=0.019). The family-based analyses identified a significant between-family component in the variance of the renal phenotypes associated with the DRD1 polymorphisms. Transmission of the DRD1 AGC haplotype was also associated with lower systolic (–3.54 mm Hg; P=0.016) and diastolic (–2.80 mm Hg; P=0.0064) BPs without significant between-family variance component. Plasma renin activity and urinary aldosterone excretion were not associated with DRD1 variation. The GRK4 Ala142Val polymorphism did not contribute to the phenotypes under study. In conclusion, renal sodium handling and BP were associated with genetic variation in the DRD1 promoter. The between-family variance component excluded population stratification for BP, but not for the renal phenotypes.

Key Words: blood pressure • clinical genetics • dopamine receptor gene • GRK4 • lithium clearance • population science • tubular transport

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