Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide.
Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide.
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DOI：
10.1186/1479-5876-10-56
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发表时间：
2012-03-22
影响因子：
7.4
通讯作者：
Johnson JA
中科院分区：
文献类型：
--
作者：
Duarte JD;Zineh I;Burkley B;Gong Y;Langaee TY;Turner ST;Chapman AB;Boerwinkle E;Gums JG;Cooper-Dehoff RM;Beitelshees AL;Bailey KR;Fillingim RB;Kone BC;Johnson JA
近三分之一的美国成年人患有高血压。氢氯噻嗪（HCTZ）是治疗高血压最常用的药物之一，其疗效参差不齐。肾上皮钠通道（ENaC）提供了微调钠排泄的机制，并且是血压稳态的主要调节器。 DOT1L、MLLT3、SIRT1 和 SGK1 编码控制组蛋白 H3 球状结构域赖氨酸 79 (H3K79) 甲基化的通路中的基因，从而调节 ENaCα 亚基的表达。本研究旨在确定这些调节基因的变异对 HCTZ 血压反应的作用，其次是未治疗血压的作用。我们在两个独立的高血压队列中研究了该候选途径的遗传变异与 HCTZ 血压反应之间的关联（clinicaltrials.gov NCT00246519 和 NCT00005520）。在二次探索性分析中，我们测量了这些相同的遗传变异与未经治疗的血压之间的关联。通过线性回归来测量关联性，只有一个队列中 P ≤ 0.01 的关联性和另一队列中 P ≤ 0.05 的重复性才被认为是显着的。在一个队列中，DOT1L (rs2269879) 的多态性与白种人对氢氯噻嗪的较高收缩压 (P = 0.0002) 和舒张压 (P = 0.0016) 反应密切相关。然而，这种关联并没有在其他队列中复制。当分析未治疗的血压水平时，我们发现 MLLT3 (rs12350051) 的多态性与未治疗的较高收缩压（两个队列中 P < 0.01）和舒张压（两个队列中 P < 0.05）血压水平之间存在方向相似的关联。然而，当在第三个高血压队列和较小的血压正常样本中尝试进一步复制时，没有观察到显着的关联。我们的数据表明 DOT1L、MLLT3、SIRT1 和 SGK1 的多态性不太可能与 HCTZ 的血压反应相关。然而，DOT1L 中的 rs2269879 可能与白种人的 HCTZ 反应相关。此外，探索性分析表明 MLLT3 中的 rs12350051 可能与非裔美国人未经治疗的血压有关。需要进行复制工作来验证这些多态性在人类血压调节中的作用。
Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCα subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure. We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ≤ 0.01 in one cohort and replication by P ≤ 0.05 in the other cohort considered significant. In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed. Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.
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影响因子：
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