Association of polymorphisms of the renin-angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough

The use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension has recently increased. However, their use is associated with a persistent dry cough in a significant percentage of such patients. The present study was designed to assess the contribution of polymorphisms as a genetic marker of ACE-inhibitor-related cough in a Japanese hypertensive population. Genotyping was carried out in 190 patients, 70 with cough and 120 without cough, who had been treated with ACE inhibitors. Polymorphisms of ACE insertion/deletion (I/D), angiotensin II type 1 receptor (1166A/C), type 2 receptor (3123C/A), and bradykinin B2 receptor (-58T/C, exon 1, I/D), were analyzed in these subjects. The TT genotype and T allele of bradykinin B2 receptor (-58T/C) were identified at a significantly higher frequency in the cough (+) patients than in the cough (-) patients. This difference was even more pronounced in women. However, there was no significant relationship between polymorphisms of ACE, angiotensin 11 receptors, or bradykinin B2 receptor exon 1, and occurrence of ACE-inhibitor-related cough. The transcriptional activity of the bradykinin B2 receptor promoter is involved in the occurrence of cough, and this new marker may provide a valuable tool to detect patients at risk of developing this side effect of ACE inhibitors. In conclusion, Susceptibility to develop cough is associated with a genetic variant of the bradykinin B2 receptor promoter; thus, it may be possible to identify those patients who will develop this adverse reaction to ACE inhibitors in advance.