Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough

Abstract

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.