Department of Anatomic Pathology, University of Barcelona, Spain.
Pharmacogenet Genomics. 2011 Sep;21(9):531-8. doi: 10.1097/FPC.0b013e328348c6db.
Dry cough is the most common reason for stopping angiotensin-converting enzyme inhibitors (ACEi) therapy. The role of ACE in the metabolism of bradykinin has been proposed as a pathogenic mechanism. This study included a complete analysis of the variability of the genes involved in bradykinin metabolism (ACE and XPNPEP2) and bradykinin receptors (BDKRB2). We included two polymorphisms in the ABO (related to ACE levels); two polymorphisms in the AGTR1, and one polymorphism in the BKRB1 (related to ACEi response).
A total of 281 patients who had been treated with ACEi were retrospectively recruited [102 patients were considered as cases (cough) and 179 patients were considered as controls (no cough)], and 56 polymorphisms were tested for association.
We found that genetic polymorphisms in BDKRB2 [rs8016905; P=0.003; odds ratio (OR)=2.21] and ABO (rs495828; P=0.001; OR=2.45) are associated with ACEi-induced cough after correction for multiple testing. The effect of polymorphisms in ABO was sex specific (female patients; P=0.0006; OR=3.26). When we analyzed the subgroup of patients homozygous GG for rs4343, two polymorphisms in the ACE were found to have protective properties (rs4459610 and rs4267385; P=0.005 and 0.004; OR=0.25). We also found a strong interaction between the ABO polymorphisms, rs495828 and rs8176746 (P<0.0001; OR=3.7).
These results highlight the importance of genetic determinants of ACE levels as good predictors of the ACEi response, and provide ABO as a good candidate gene for pharmacogenetic studies of ACEi-related cough. Moreover, our results also confirm the importance of bradykinin in the pathogenesis of this adverse effect.
干咳是停止血管紧张素转换酶抑制剂（ACEi）治疗的最常见原因。ACE 在缓激肽代谢中的作用被认为是一种致病机制。本研究对参与缓激肽代谢（ACE 和 XPNPEP2）和缓激肽受体（BDKRB2）的基因的变异性进行了全面分析。我们纳入了与 ACE 水平相关的 ABO 中的两个多态性；AGTR1 中的两个多态性和 BKRB1 中的一个多态性（与 ACEi 反应相关）。
回顾性招募了 281 名接受 ACEi 治疗的患者[102 例被认为是病例（咳嗽），179 例被认为是对照组（无咳嗽）]，并对 56 个多态性进行了关联测试。
我们发现 BDKRB2 中的遗传多态性[rs8016905；P=0.003；比值比（OR）=2.21]和 ABO（rs495828；P=0.001；OR=2.45）与 ACEi 诱导的咳嗽相关，经多重检验校正后。ABO 多态性的作用具有性别特异性（女性患者；P=0.0006；OR=3.26）。当我们分析 rs4343 纯合 GG 患者的亚组时，发现 ACE 中的两个多态性具有保护作用（rs4459610 和 rs4267385；P=0.005 和 0.004；OR=0.25）。我们还发现 ABO 多态性 rs495828 和 rs8176746 之间存在强烈的相互作用（P<0.0001；OR=3.7）。
这些结果强调了 ACE 水平的遗传决定因素作为 ACEi 反应良好预测因子的重要性，并提供 ABO 作为 ACEi 相关咳嗽的药物遗传学研究的候选基因。此外，我们的结果还证实了缓激肽在这种不良反应发病机制中的重要性。
