鉴定与血管紧张素转换酶抑制剂诱导的咳嗽易感性相关的遗传因素。

Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough.

机构信息

Unidad de Hipertensión, Servicio de Medicina Interna, Hospital Universitario de Valme, Carretera de Cádiz S/N bNeocodex, Avda, Charles Darwin, Acc. A. Seville, Spain.

出版信息

Pharmacogenet Genomics. 2011 Jan;21(1):10-7. doi: 10.1097/FPC.0b013e328341041c.

DOI:10.1097/FPC.0b013e328341041c

PMID:21052031

Abstract

BACKGROUND AND OBJECTIVE

Angiotensin-converting enzyme inhibitors (ACEi) are the first selected drugs for hypertensive patients because of its protective properties against heart and kidney diseases. Persistent cough is a common adverse reaction associated with ACEi, which can bind to the treatment cessation, but its etiology remains an unresolved issue. The most accepted mechanism is that the inhibition of ACEi increases kinins levels, resulting in the activation of proinflammatory mechanisms and nitric oxide generation. However, relatively little is known about the genetic susceptibility to ACEi-induced cough in hypertensive patients.

METHODS

We carried out a monogenic association analysis of 39 polymorphisms and haplotypes in genes encoding key proteins related to ACEi activity with the occurrence of ACEi-induced cough. We also carried out a digenic association analysis and investigated the existence of epistatic interactions between the analyzed polymorphisms using a logistic regression procedure. Finally, we investigated the predictive value of the identified associations for ACEi-induced cough.

RESULTS

We found that genetic polymorphisms in MME [rs2016848, P=0.002, odds ratio (OR)=1.795], BDKRB2 (rs8012552, P=0.012, OR=1.609), PTGER3 (rs11209716, P=0.002, OR=0.565), and ACE (rs4344) genes are associated with ACEi-related cough. For the latter, the effect is sex specific, having a protective effect in males (P=0.027, OR=0.560) and increasing the risk in females (P=0.031, OR=1.847). In addition, genetic interactions between peptidases involved in kinins levels (CPN1 and XPNPEP1) and proteins related to prostaglandin metabolism (PTGIS and PTGIR) strongly modify the risk of ACEi-induced cough presentation (0.102≤OR≤0.384 for protective combinations and 2.732≤OR≤7.216 for risk combinations).

CONCLUSION

These results are consistent with the hypothesis that the mechanism of cough is related to the accumulation of bradykinin, substance P, and prostaglandins.

摘要

背景和目的

血管紧张素转换酶抑制剂（ACEi）因其对心脏和肾脏疾病的保护作用，是高血压患者的首选药物。持续性咳嗽是 ACEi 常见的不良反应，可导致治疗中断，但病因仍未解决。最被接受的机制是 ACEi 的抑制增加激肽水平，导致促炎机制和一氧化氮的产生激活。然而，关于高血压患者 ACEi 诱导性咳嗽的遗传易感性，人们知之甚少。

方法

我们对编码与 ACEi 活性相关的关键蛋白的基因中的 39 个多态性和单倍型进行了单基因关联分析，以研究 ACEi 诱导性咳嗽的发生。我们还进行了双基因关联分析，并使用逻辑回归程序研究了分析多态性之间是否存在上位性相互作用。最后，我们研究了鉴定关联对 ACEi 诱导性咳嗽的预测价值。

结果

我们发现，MME [rs2016848，P=0.002，优势比（OR）=1.795]、BDKRB2（rs8012552，P=0.012，OR=1.609）、PTGER3（rs11209716，P=0.002，OR=0.565）和 ACE（rs4344）基因中的遗传多态性与 ACEi 相关的咳嗽有关。对于后者，其作用具有性别特异性，在男性中具有保护作用（P=0.027，OR=0.560），而在女性中则增加了风险（P=0.031，OR=1.847）。此外，涉及激肽水平的肽酶（CPN1 和 XPNPEP1）和与前列腺素代谢相关的蛋白质（PTGIS 和 PTGIR）之间的遗传相互作用强烈改变 ACEi 诱导性咳嗽表现的风险（保护性组合的 OR 为 0.102≤0.384，风险组合的 OR 为 2.732≤0.721）。