Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama 55294-0022, USA.
Pharmacogenet Genomics. 2012 May;22(5):355-66. doi: 10.1097/FPC.0b013e3283516ff8.
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 individuals on the basis of their genetic profile who benefit most from a particular treatment.
Candidate genetic variants (n=78) were genotyped in 39 114 participants from Genetics of Hypertension Associated Treatment study, ancillary to Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial randomized hypertensive participants (≥55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or nonfatal myocardial infarction (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. Receiver-operating characteristic (ROC) curves estimated the discrimination rate between those with and without a CHD event, on the basis of the addition of the genetic panel risk score.
For each treatment group, we identified a panel of genetic variants that collectively improved the 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=0.004; Amlodipine (B): MMP1 rs1799750; Factor5 (F5) rs6025; NPPA rs5065; PDE4D rs6450512; MMP9 rs2274756; ROC comparison, P=0.006; Lisinopril (C): AGT rs5051; PON1 rs705379; MMP12 rs652438; F12 rs1801020; GP1BA rs6065; PDE4D rs27653; ROC comparison, P=0.01; Doxazosin (D): F2 rs1799963; PAI1 rs1799768; MMP7 rs11568818; AGT rs5051; ACE rs4343; MMP2 rs243865; ROC comparison, P=0.007. Each panel was tested for a pharmacogenetic effect; panels A, B, and D showed such evidence (P=0.009, 0.006, and 0.001, respectively) and panel C did not (P=0.09).
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.
确定预测高血压患者接受四种不同初始降压治疗之一的治疗相关冠心病（CHD）结局的遗传变异面板。目标是根据患者的基因谱确定从特定治疗中获益最大的亚组个体。
候选遗传变异（n=78）在来自高血压相关治疗遗传学研究的 39114 名参与者中进行了基因分型，该研究是抗高血压和降脂治疗预防心脏病发作试验的辅助研究。抗高血压和降脂治疗预防心脏病发作试验将高血压参与者（≥55 岁）随机分配到四种治疗方法（氨氯地平、氯噻酮、多沙唑嗪、赖诺普利）之一。主要结局是致命性 CHD 或非致死性心肌梗死（平均随访=4.9 年）。在每个治疗组内推导出一个药物遗传学面板。基于加性遗传面板风险评分，接收者操作特征（ROC）曲线估计了 CHD 事件患者与无 CHD 事件患者之间的区分率。
对于每个治疗组，我们确定了一组遗传变异，这些变异共同在一定程度上提高了 CHD 的预测准确性。氯噻酮（A）：NOS3 rs3918226；SELE rs5361；ICAM1 rs1799969；AGT rs5051；GNAS rs7121；ROC 比较，P=0.004；氨氯地平（B）：MMP1 rs1799750；Factor5（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=0.01；多沙唑嗪（D）：F2 rs1799963；PAI1 rs1799768；MMP7 rs11568818；AGT rs5051；ACE rs4343；MMP2 rs243865；ROC 比较，P=0.007。每个面板均经过药物遗传学效应测试；面板 A、B 和 D 显示出这种证据（P=0.009、0.006 和 0.001），而面板 C 则没有（P=0.09）。
由于每个面板与特定治疗组的 CHD 相关，但与其他组不相关，因此该研究提供了证据，表明可能使用基因面板评分作为工具，以更好地评估降压治疗选择，从而降低高血压患者的 CHD 风险。
