Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study.
Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study.
复制标题
DOI：
10.1097/fpc.0b013e3283516ff8
复制
发表时间：
2012-05
影响因子：
2.6
通讯作者：
Arnett DK
中科院分区：
文献类型：
--
作者：
Lynch AI;Eckfeldt JH;Davis BR;Ford CE;Boerwinkle E;Leiendecker-Foster C;Arnett DK
确定预测高血压患者在四种不同类型的初始抗高血压治疗中的一种治疗相关冠心病（CHD）结局的遗传变异组。其目标是根据遗传特征确定从特定治疗中获益最多的人群。候选遗传变异（n=78）在来自GenHAT的39114名参与者中进行了基因分型。ALLHAT将高血压患者（>=55岁）随机分为四组（氨氯地平、氯噻酮、多沙唑嗪、赖诺普利）。主要结局为致死性冠心病或非致死性心肌梗死（平均随访4.9年）。在四个治疗组中分别建立了药理学小组。ROC曲线估计有和没有冠心病事件的人之间的辨别率，基于遗传面板风险评分的增加。对于每个治疗组，我们确定了一组遗传变异，这些变异在很小但具有统计学意义的程度上共同提高了冠心病的预测。氯噻酮(A): NOS3, rs3918226；希利,rs5361;ICAM1 rs1799969;AGT rs5051;玲娜,rs7121;ROC比较p= 0.004；氨氯地平(B): MMP1, rs1799750；F5, rs6025;NPPA rs5065;PDE4D rs6450512;MMP9, rs2274756;ROC比较p= 0.006；赖诺普利(C): AGT, rs5051；PON1 rs705379;MMP12 rs652438;F12 rs1801020;GP1BA rs6065;PDE4D rs27653;ROC比较p=.01；Doxazosin (D): F2, rs1799963；PAI1 rs1799768;MMP7 rs11568818;AGT rs5051;王牌,rs4343;MMP2 rs243865;ROC比较p=.007。每个小组都进行了药理学效应测试；组A， B和D显示了这样的证据(p= 0.009，。006，和。0.001)， C组没有（p=.09）。因为在特定的治疗组中，每个基因组都与冠心病相关，而在其他治疗组中则不相关，因此本研究提供了证据，表明可以使用基因组评分作为一种工具，更好地评估抗高血压治疗选择，以降低高血压个体的冠心病风险。
To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of people based on their genetic profile who benefit most from a particular treatment. Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score. For each treatment group, we identified a panel of genetic variants that collectively improved prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3, rs3918226; SELE, rs5361; ICAM1, rs1799969; AGT, rs5051; GNAS, rs7121; ROC comparison p=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.09). Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.