title: Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough: the role of ACE, ABO, and BDKRB2 genes.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anatomic Pathology, University of Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Mas
authors.forename: Patricia
authors.initials: P
authors.lastname: Gassò
authors.forename: Santiago
authors.initials: S
authors.lastname: Alvarez
authors.forename: Jacint
authors.initials: J
authors.lastname: Ortiz
authors.forename: Jose M
authors.initials: JM
authors.lastname: Sotoca
authors.forename: Antonio
authors.initials: A
authors.lastname: Francino
authors.forename: Xavier
authors.initials: X
authors.lastname: Carne
authors.forename: Amalia
authors.initials: A
authors.lastname: Lafuente
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D003371:Cough / Q000139:chemically induced* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D016695:Glycosyltransferases / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D043782:Receptor, Bradykinin B2 / Q000235:genetics*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D054316:Biomarkers, Pharmacological; D043782:Receptor, Bradykinin B2; D016695:Glycosyltransferases; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A