ASSOCIATION OF CYP3A5 GENOTYPES WITH BLOOD PRESSURE AND RENAL FUNCTION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。肾脏细胞色素P450 3A 5（CYP 3A 5）活性与人类的血压和盐敏感性相关。我们确定了CYP 3A 5多态性是否与非洲家庭的动态血压（ABP）和肾小球滤过率（GFR）相关。采用横断面设计，375个人从72个家庭，每个家庭至少有两个高血压的兄弟姐妹，通过高血压登记在塞舌尔（印度洋）招募。我们分析了CYP 3A 5等位基因与ABP、GFR和肾钠处理（锂排泄分数）之间的关联，从系谱数据中，考虑到其他协变量和家族相关性。CYP 3A 5携带者的日间收缩压和舒张压随年龄的增加（0.55和0.23 mmHg/年）高于非携带者（0.21和0.04 mmHg/年）。CYP 3A 5对日间收缩压/舒张压ABP有显著的主效应[回归系数（SE）：分别为-29.6（10.0）/-8.2（4.1）mmHg，P =0.003/0.045]，该效应受年龄影响（CYP 3A 5 x年龄相互作用，P =0.017/0.018）。对于夜间ABP，尿钠排泄改变了CYP 3A 5的作用，而不是年龄。对于肾功能，CYP 3A 5携带者的GFR比非携带者低7.6（3.8）ml/min（P=0.045）。非携带者的近端钠重吸收随年龄增长而下降，但CYP 3A 5携带者（相互作用P = 0.02）。这些数据表明CYP 3A 5多态性与动态血压相关，CYP 3A 5携带者的ABP显示出比非携带者更高的年龄和钠相关性增加。年龄效应可能部分归因于CYP 3A 5对肾钠处理的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associted with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. CYP3A5 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P =0.003/0.045, respectively] and this effect was modified by age (CYP3A5 x age interactions, P =0.017/0.018). For night-time ABP, the effect of CYP3A5 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5 carriers had a 7.6(3.8) ml/min lower GFR(P=0.045) than non-carriers, Proximal sodium reabsorption decreased with age in non-carriers, but in CYP3A5 carriers (P for interaction = 0.02). These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.