Department of Cardiology, Erasmus MC, Thoraxcenter, 's Gravendijkwal 230, Rotterdam, The Netherlands.
Eur Heart J. 2010 Aug;31(15):1854-64. doi: 10.1093/eurheartj/ehq169. Epub 2010 Jun 10.
The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors.
In 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5% of the patients [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5% (HR 1.26; 95% CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed.
The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.
血管紧张素转换酶（ACE）抑制剂在稳定型冠状动脉疾病（CAD）中的疗效可能通过将治疗靶向最有可能受益的患者来增强。然而，这些患者无法通过临床特征来识别。我们开发了一种遗传谱来预测 ACE 抑制剂治疗获益的存在，并优化 ACE 抑制剂的治疗。
在参加随机安慰剂对照 EUROPA 试验的 8907 例稳定型 CAD 患者中，我们分析了 ACE 抑制剂药效学途径中的 12 个候选基因，使用了 52 个单核苷酸多态性（SNP）的单倍型标签。主要终点是在 4.2 年的随访期间心血管死亡率、非致死性心肌梗死和复苏性心脏骤停的减少。使用置换分析进行了多变量 Cox 回归分析，并进行了多次测试校正。三个位于血管紧张素 II 型 1 型受体和缓激肽 1 型受体基因中的多态性在经过多变量调整混杂因素和多次测试校正后，与培哚普利治疗的获益显著相关。结合这三个 SNP 的药物遗传学评分显示，在安慰剂组中风险呈逐步降低趋势，随着评分的增加，培哚普利的治疗获益呈逐步降低趋势（交互 P < 0.0001）。在患者中观察到明显的治疗益处亚组为 73.5%（危险比[HR]0.67；95%置信区间[CI]0.56-0.79），而其余 26.5%（HR1.26；95%CI0.97-1.67）则无获益趋势，并且存在有害影响的趋势。在 PROGRESS 试验中接受培哚普利或安慰剂治疗的 1051 例脑血管疾病患者中，观察到方向和幅度相似的交互作用效应，但无统计学意义。
本研究首次确定了 ACE 抑制剂治疗获益的遗传决定因素。我们开发了一种遗传谱，可以预测 ACE 抑制剂的治疗获益，并可用于优化治疗。
