Blood pressure and renal sodium handling in relation to genetic variation in the DRD1 promoter and GRK4
Blood pressure and renal sodium handling in relation to genetic variation in the DRD1 promoter and GRK4
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DOI：
10.1161/hypertensionaha.107.109611
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发表时间：
2008-06-01
期刊：
影响因子：
8.3
通讯作者：
Brand, Eva
中科院分区：
文献类型：
--
作者：
Staessen, Jan A.;Kuznetsova, Tatiana;Brand, Eva
1型多巴胺受体（DRD1）的激活减少了肾脏钠的重吸收。在一个以家庭为基础的随机样本中，611名未经治疗的白人（女性，45.0%，平均年龄，38.6岁），我们测量了血压（BP）。我们使用内源性锂清除率来评估部分钠排泄（FENa）和近端（RNaprox）和远端（RNadist）管状钠重吸收。我们研究了DRD1启动子（A-48G、G-94A和C-800T）和GRK4 （Ala142Val）与多变量调整的相关性。常见的DRD1单倍型为AGC（48.2%）、GGT（34.4%）和AAC（14.3%）。在标准化平均钠排泄量（8.7 mmol/h）并调整协变量和相关性后，RNadist在DRD1 -94GG纯合子中低于-94A等位基因携带者（效应值为-0.94%，P=0.005），而在FENa中则相反（+0.084%，P=0.014）。AGC携带者（-0.88%，P=0.012）和AAC携带者（+1.00%，P=0.004）的RNadist与相应的非携带者相比存在差异。此外，AAC携带者的fea低于非携带者（-0.082%；P=0.019）。基于家族的分析确定了与DRD1多态性相关的肾脏表型差异的显著家族间成分。DRD1 AGC单倍型的传播也与较低的收缩压（-3.54 mm Hg， P=0.016）和舒张压（-2.80 mm Hg， P=0.0064） bp相关，没有显著的家族间方差成分。血浆肾素活性和尿醛固酮排泄与DRD1变异无关。GRK4 Ala142Val多态性与所研究的表型无关。总之，肾脏钠处理和血压与DRD1启动子的遗传变异有关。家族间方差排除了BP的人群分层，但不排除肾脏表型的人群分层。
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 (FENa) and proximal (RNaprox) and distal (RNadist) 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, RNadist was lower in DRD1 -94GG homozygotes than -94A allele carriers ( effect size, -0.94%; P=0.005) with opposite findings for FENa (+0.084%; P=0.014). AGC carriers (-0.88%; P=0.012) and AAC carriers (+1.00%; P=0.004) had different RNadist compared to corresponding noncarriers. Furthermore, FENa 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.