Brugts J J, de Maat M P M, Boersma E, Witteman J C M, van Duijn C, Uitterlinden A G, Bertrand M, Remme W, Fox K, Ferrari R, Danser A H J, Simoons M L
Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Cardiovasc Drugs Ther. 2009 Apr;23(2):171-81. doi: 10.1007/s10557-008-6156-1. Epub 2008 Dec 10.
Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage.
The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at -40 degrees C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (promoter) and existing relevant literature. The main outcome measure of PERGENE is the effect of genetic factors on the treatment benefit with ACE-inhibitors. The size of this pharmacogenetic substudy allows detection with a statistical power of 98% to detect a difference in hazard ratios (treatment effect) of 20% between genotypes with minor allele frequency of 0.20 (two-sided alpha 0.05).
The PERGENE study is a large cardiovascular pharmacogenetic study aimed to assess the feasibility of pharmacogenetic profiling of the treatment effect of ACE-inhibitor use with the perspective to individualize treatment in patients with stable coronary artery disease.
血管紧张素转换酶（ACE）抑制剂可减轻高血压、心力衰竭和稳定型冠状动脉疾病（CAD）患者的临床症状并改善其预后，是这些患者群体中最常用的药物之一。对于高血压，治疗以血压水平为指导。在二级预防中，尚无指导治疗的方法。此前将ACE抑制剂靶向最可能受益患者的尝试未获成功，主要原因是临床亚组中治疗效果的一致性。然而，对于ACE抑制剂的长期预防性治疗，最好仅针对最可能受益的患者进行治疗，这将大幅降低所需治疗人数并提高成本效益。一种新的“量身定制疗法”方法可能是整合患者间基因变异的信息。到目前为止，ACE抑制剂治疗CAD患者疗效的药物遗传学研究仍处于初步阶段。
培哚普利基因关联研究（PERGENE）是EUROPA试验的一项子研究，EUROPA试验是一项随机双盲安慰剂对照多中心临床试验，该试验证明ACE抑制剂培哚普利在降低12218例稳定型冠状动脉疾病患者的心血管发病率和死亡率方面具有有益作用（平均随访4.2年）。在EUROPA试验开始时从患者处采集血样管，血沉棕黄层保存在中央核心实验室的-40℃环境中。在肾素-血管紧张素系统和缓激肽途径中选择候选基因。根据单倍型标签原则，利用HapMap基因组计划、西雅图和其他最新的基因数据库平台选择多态性，以全面覆盖基因内所有常见的基因变异。选择时还考虑了单核苷酸多态性（SNP）的功能、在基因（启动子）内的位置以及现有相关文献。PERGENE的主要结局指标是基因因素对ACE抑制剂治疗获益的影响。这项药物遗传学子研究的规模使其具有98%的统计检验效能，以检测次要等位基因频率为0.20的基因型之间风险比（治疗效果）20%的差异（双侧α 0.05）。
PERGENE研究是一项大型心血管药物遗传学研究，旨在评估ACE抑制剂治疗效果的药物遗传学分析的可行性，以期实现稳定型冠状动脉疾病患者的个体化治疗。
