Blood pressure and renal sodium handling in relation to genetic variation in the DRD1 promoter and GRK4.
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.
Staessen
Jan A
JA
Genetic Epidemiology Unit, Department of Epidemiology, University of Maastricht, The Netherlands. ja.staessen@epid.unimaas.nl
Kuznetsova
Tatiana
T
Zhang
Haifeng
H
Maillard
Marc
M
Bochud
Murielle
M
Hasenkamp
Sandra
S
Westerkamp
Judith
J
Richart
Tom
T
Thijs
Lutgarde
L
Li
Xinli
X
Brand-Herrmann
Stefan-Martin
SM
Burnier
Michel
M
Brand
Eva
E
D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D005192:Family Health; D005260:Female; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006977:Hypertension, Renal / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008094:Lithium / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D012964:Sodium / Q000378:metabolism*
D017447:Receptors, Dopamine D1; D008094:Lithium; D012964:Sodium; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human