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

作者：Antonio Grilo, María P. Sáez-Rosas, Juan Santos-Morano, Elena Sánchez, Concha Moreno‐Rey, Luís Miguel Real, Reposo Ramírez‐Lorca, María Eugenia Sáez · 发表于：Pharmacogenetics and Genomics · 年份：2010 · DOI：10.1097/fpc.0b013e328341041c · 被引用次数：56 · 研究领域：Respiratory and Cough-Related Research、Asthma and respiratory diseases、Renin-Angiotensin System Studies

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=0.0...