Effects Of COX-2, ABO And NR3C2Genetic Polymorphisms On Cough And Efficacy Of Enalapril

Backgrounds and Aims:Angiotensin Converting Enzyme Inhibitors (ACEI) have been prescribed for more than30years, are the only one with six kinds of strong indications including heart failure, myocardial infarction, coronary heart disease, diabetes, chronic kidney disease and prevention of stroke recurrence. A large amount of data shows that the antihypertensive effect and adverse reaction of these drugs vary greatly among individuals. Pharmacogenetics and pharmacogenomics research indicates that genetic factors play a determinant role in drug efficacy and adverse reaction.Angiotensin-converting enzyme and inflammation play a critical role in the pathogenic mechanism of ACEI-induced cough. Aldosterone in the downstream of RAAS exerts its major effects by binding to the Mineralocorticoid receptor (MR). The products encoded by COX-2and ABO gene exert an important impact on the inflamation and angiotensin-converting enzyme. The aims of our study were to determine the effects of COX-2and ABO genetic polymorphisms on enalapril-induced cough and to evaluate the association of NR3C2genetic polymorphisms with the therapeutic efficacy of enalapril in Chinese essential hypertension patients. The study aims to explore the possible pharmacogenetics factors on the antihypertensive efficacy of enalapril treatment and thus to provide individualized therapy of enalapril with new ideas and new methods ultimately.Patients&methods:A total of450hypertensive patients aged45to70treated with lOmg enalapril maleate once a day for two weeks were genotyped for COX-2-1290A>G,-1195G>A and8473T>C polymorphisms using PCR-RFLP assays and ABO polymorphisms using PCR-direct sequencing.279patients were enrolled and given enalapril lOmg once a day for two weeks to explore the association of the antihypertensive response to enalapril with NR3C2genetic polymorphisms. NR3C2tagSNPs (rs5522, rs2070950) were selected and determined by the MassARRAY assay.Results:Thirty-two percent (144/450) patients suffered from enalapril-induced cough. In males,COX-2-1195AA genotype conferred an increased risk of enalapril-induced cough (OR=3.57[1.05,12.13]) and the frequency of AAT haplotype (-1290A>G/-1195G>A/8473T>C) in coughers was significantly higher than that in controls (P=0.016). However, the three COX-2SNPs and haplotypes were not associated with enalapril-induced cough in females. Thirteen SNPs in the ABO gene were observed by direct sequencing. According to the results of linkage disequilibrium analysis, four ABO variations, rs8176746, rs8176740, rs495828and rs12683493, were chosen to evaluate the association between ABO genetic polymorphisms and enalapril-induced cough. The distribution of rs8176740and rs495828is significantly different between the coughers and controls(P=0.0388, P=0.0183) while no significant difference in the distributions of rs8176746and rs12683493is observed between coughers and controls. The risk of enalapril-induced cough in the rs495828TT carriers was2.7times higher than the others after adjusting the potential confounders such as age, gender, smoking status and alcohol habits using an unconditional logistic regression model(OR=2.69;95%CI=1.22,5.95;P=0.008). There is a marginally significant difference between the rs8176740TT genotype and other genotypes (OR=0.43;95%CI=0.16,1.17; P=0.092). Haplotype analysis in between rs8176746and rs8176740in the exon7indicated the frequencies of GA haplotype was significantly higher in coughers than those in the controls (58.4%vs49.7%, P=0.017). Haplotype analysis in between rs495828and rsl2683493in the promoter region indicated the frequencies of GC haplotype was significantly lower in coughers than those in the controls (61.2%vs69.8%, P=0.008) while the frequencies of TC haplotype was significantly higher in coughers than those in the controls (26.6%vs19.1%, P=0.013). Haplotype analysis in the four ABO variations (rs8176746/rs8176740/rs495828/rs12683493) showed that the frequencies of GATC haplotype was significantly higher in coughers than those in the controls (26.6%vs18.8%, P=0.009) and the frequencies of GTGC haplotype was significantly lower in coughers than those in the controls (21.8%vs28.7%, P=0.029).The frequencies of the two minor alleles (rs5522, rs2070950) were15%,24.5%respectively and were different in ethnics. After2weeks of treatment, the reductions in DBP were significantly greater in AA genotype carriers compared with AG+GG genotype carriers(P=0.009) while the reductions in DBP were greater in GG genotype carriers compared with GC+CC genotype carriers, with marginal significance (P=0.065). Rs5522is stilt a significant predictor of DBP reduction, adjusting age, BMI, basic blood pressure, sex, WHR and rs2070950genotype by stepwise multiple linear regression analysis (P=0.003).Conclusion:COX-2-1195G>A polymorphism and AAT haplotype were associated with enalapril-induced cough in men but not women. ABO rs495828and rs8176740were associated with enalapril-induced cough. NR3C2rs5522may be a determinant of the blood pressure response to enalapril treatment in hypertensive patients.