Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough: the role of ACE, ABO, and BDKRB2 genes.

BACKGROUND AND 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). CONCLUSION: 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.

A common variant of the ABO gene protects against hypertension in a Spanish population.

The objective of this study was to establish whether genetic polymorphisms that could be related to angiotensin-converting enzyme (ACE) levels are associated with hypertension. A total of 10 haplotype-tagging single-nucleotide polymorphisms in ACE, the ACE I/D polymorphism, and 2 polymorphisms in the ABO (rs495828 and rs8176746) were investigated for association with hypertension in 269 hypertensive patients and 254 healthy controls. All analyses were adjusted for age and body mass index, and corrected for multiple testing. Only one polymorphism of the ABO gene (rs495828) presented nominal pointwise P<0.05 values (odds ratio = 0.33, 95% CI 0.19-0.58, P = 6 × 10(-5)) and achieved P<3.8 × 10(-3), the nominal P-value considered significant after Bonferroni correction. Analysis of the genotype frequencies showed that the model that correctly explained the observed association was the recessive model (odds ratio = 0.03, 95% CI 0.01-0.15, P = 1 × 10(-6)). These results indicate that genetic variants that could be related to ACE activity are good predictors of hypertension, and identify ABO as a good candidate gene for genetic studies of hypertension risk. Further studies are required to confirm this association.

Randomized clinical trial of the effectiveness of a home-based intervention in patients with heart failure: the IC-DOM study.

INTRODUCTION AND OBJECTIVES: The objective of this study was to determine whether a home-based intervention can reduce mortality and hospital readmissions and improve quality of life in patients with heart failure. METHODS: A randomized clinical trial was carried out between January 2004 and October 2006. In total, 283 patients admitted to hospital with a diagnosis of heart failure were randomly allocated to a home-based intervention (intervention group) or usual care (control group). The primary end-point was the combination of all-cause mortality and hospital readmission for worsening heart failure at 1-year follow-up. RESULTS: The primary end-point was observed in 41.7% of patients in the intervention group and in 54.3% in the control group. The hazard ratio was 0.70 (95% confidence interval [CI] 0.55-0.99). Taking significant clinical variables into account slightly reduced the hazard ratio to 0.62 (95% CI 0.50-0.87). At the end of the study, the quality of life of patients in the intervention group was better than in the control group (18.57 vs. 31.11; P< .001). CONCLUSIONS: A home-based intervention for patients with heart failure reduced the aggregate of mortality and hospital readmissions and improved quality of life.