Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Clin Endocrinol (Oxf). 2011 Jun;74(6):783-90. doi: 10.1111/j.1365-2265.2011.03991.x.
25-Hydroxyvitamin D (25(OH)D) deficiency and excess activity of the renin-angiotensin system (RAS) are both associated with cardiovascular disease. Vitamin D interacts with the vitamin D receptor (VDR) to negatively regulate renin expression in mice; however, human studies linking genetic variation in the VDR with renin are lacking. We evaluated (i) whether genetic variation in the VDR at the Fok1 polymorphism was associated with plasma renin activity (PRA) in a population of hypertensives and a separate population of normotensives and (ii) whether the association between Fok1 genotype and PRA was independent of 25(OH)D levels.
DESIGN/PATIENTS/MEASUREMENTS: Genetic association study, assuming an additive model of inheritance, of 375 hypertensive and 146 normotensive individuals from the HyperPATH cohort, who had PRA assessments after 1 week of high dietary sodium balance (HS) and l week of low dietary sodium balance (LS).
The minor allele (T) at the Fok1 polymorphism was significantly associated with lower PRA in hypertensives (LS: β = -0·22, P < 0·01; HS: β = -0·19, P < 0·01); when repeated in normotensives, a similar relationship was observed (LS: β = -0·17, P < 0·05; HS: β = -0·18, P = 0·14). In multivariable analyses, both higher 25(OH)D levels and the T allele at Fok1 were independently associated with lower PRA in hypertensives; however, 25(OH)D was not associated with PRA in normotensives.
Genetic variation at the Fok1 polymorphism of the VDR gene, in combination with 25(OH)D levels, was associated with PRA in hypertension. These findings support the vitamin D-VDR complex as a potential regulator of renin activity in humans.
25-羟维生素 D（25（OH）D）缺乏和肾素-血管紧张素系统（RAS）过度活跃均与心血管疾病有关。维生素 D 与维生素 D 受体（VDR）相互作用，负调节小鼠肾素的表达；然而，缺乏与 VDR 基因变异相关的人类研究。我们评估了（i）在高血压人群和正常血压人群中，VDR 中的 Fok1 多态性的基因变异是否与血浆肾素活性（PRA）相关，以及（ii）Fok1 基因型与 PRA 之间的关联是否独立于 25（OH）D 水平。
设计/患者/测量：遗传关联研究，假设遗传的加性模型，对 HyperPATH 队列中的 375 名高血压患者和 146 名正常血压患者进行研究，这些患者在高膳食钠平衡（HS）后 1 周和低膳食钠平衡（LS）后 1 周进行了 PRA 评估。
Fok1 多态性的次要等位基因（T）与高血压患者的 PRA 显著相关（LS：β=-0.22，P<0.01；HS：β=-0.19，P<0.01）；在正常血压患者中重复该研究时，观察到类似的关系（LS：β=-0.17，P<0.05；HS：β=-0.18，P=0.14）。在多变量分析中，25（OH）D 水平较高和 Fok1 的 T 等位基因均与高血压患者的 PRA 降低独立相关；然而，25（OH）D 与正常血压患者的 PRA 无关。
VDR 基因 Fok1 多态性的遗传变异与高血压患者的 PRA 相关，结合 25（OH）D 水平。这些发现支持维生素 D-VDR 复合物作为人类肾素活性的潜在调节剂。
