Gender differences in impact of CYP2C19 polymorphism on development of coronary artery disease.

The aim was to clarify whether CYP2C19 polymorphism is associated with the development of coronary artery disease (CAD). This study enrolled 723 patients with CAD (men 71%, 70 years) and healthy subjects undergoing a medical checkup (n = 453) as controls (men 69%, 53 years). We analyzed the incidence of CYP2C19 polymorphism and its association with the development of CAD in the absence of diabetes, dyslipidemia, and chronic kidney disease to minimize the influence of conventional coronary risk factors. In the analysis without risk factors, there was no difference in the incidence of the CYP2C19 genotype between CAD (n = 115) and control (n = 194) groups [extensive metabolizer, intermediate metabolizer, poor metabolizer (PM) in non-risk CAD: 33%, 46%, 21%, respectively; in non-risk control: 31%, 52%, 17%, respectively]. Analysis between CAD and control groups by the χ test showed that there was significant difference in distribution of CYP2C19 genotype in women alone (P = 0.025) but not in total subjects (P = 0.471) or men (P = 0.678), respectively. CYP2C19 PM was an independent predictor of CAD risk in women alone (odds ratio, 10.717; 95% confidence interval, 1.753-65.505; P = 0.010) but not in men. CYP2C19 PM status might be associated with the development of CAD as a disease susceptibility gene, especially in women.

Beta-3-adrenergic Receptor rs4994 Polymorphism Is a Potential Biomarker for the Development of Nonalcoholic Fatty Liver Disease in Overweight/Obese Individuals.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. Obesity is the most common and well-established risk factor for NAFLD, but there are large interindividual differences in the relationship between weight status and the development of NAFLD. Beta-3-adrenergic receptor (ADRB3) plays a key role in the development of visceral obesity and insulin resistance; however, the effect of ADRB3 polymorphisms on the risk of NAFLD remains unclear. We investigated whether or not a common rs4994 polymorphism (T190C) in the ADRB3 gene is associated with the risk of NAFLD through an increase in the body mass index (BMI) among the general population. We performed cross-sectional and longitudinal analyses in a total of 591 Japanese health screening program participants. Among the overweight or obese subjects, but not normal-weight subjects, individuals with the C/C genotype had a higher risk of developing NAFLD in comparison to those with other genotypes in the cross-sectional analysis (odds ratio: 4.40, 95% confidence interval (CI): 1.08-17.93). Meanwhile, the receiver operating characteristic curve indicated that the association between an increase in the BMI and the presence of NAFLD in subjects with the C/C genotype (area under the curve: 0.91, 95% CI: 0.78-1.00) was more pronounced in comparison to subjects with other genotypes. These above-described findings were verified by the analyses using a replicated data set consisting of 5,000 random samples from original data sets. Furthermore, among the 291 subjects for whom longitudinal medical information could be collected and who did not have NAFLD at baseline, the Cox proportional hazard model also confirmed that overweight or obese status and the C/C genotype were concertedly related to the increased risk of NAFLD development. These results suggest that genotyping the ADRB3 rs4994 polymorphism may provide useful information supporting the development of personalized BMI-based preventive measures against NAFLD.

Patients with both CYP2C19 loss-of-function allele and peripheral endothelial dysfunction are significantly correlated with adverse cardiovascular events following coronary stent implantation.

BACKGROUND: There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients receiving dual antiplatelet therapy (DAPT). Peripheral endothelial dysfunction has recently been reported to predict adverse cardiovascular events. We hypothesized that CYP2C19 loss-of-function (LOF) allele carriers with peripheral endothelial dysfunction had worse prognosis. The aim of this study was to evaluate an additive effect of peripheral endothelial dysfunction on clinical outcome following percutaneous coronary intervention (PCI) in patients with a CYP2C19 variant. METHODS: We enrolled 434 patients on DAPT following PCI. CYP2C19 genotype was examined, and we divided patients into two groups: carriers, who had at least one CYP2C19 LOF allele, and non-carriers. Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low and high RHI. Thus, subjects were divided into four groups, and clinical events were followed up. RESULTS: A total of 55 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers with low RHI (log-rank test: p=0.007). Multivariate Cox proportional hazards analysis identified both CYP2C19 LOF allele possession (hazard ratio (HR): 1.94; 95% confidence interval (CI): 1.1-3.69; p=0.045) and low RHI (HR: 2.15; 95% CI: 1.22-3.78; p=0.008) as independent and significant predictors of future cardiovascular events. CONCLUSIONS: CYP2C19 LOF allele carriers with peripheral endothelial dysfunction were significantly correlated with cardiovascular events. The additional evaluation of peripheral endothelial function along with CYP2C19 polymorphism might improve risk stratification after coronary stent implantation.

Combined effects of current-smoking and the aldehyde dehydrogenase 2*2 allele on the risk of myocardial infarction in Japanese patients.

Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes, e.g. acetaldehyde in cigarette smoke; however, the interactive effects between smoking status and the ALDH2 genotype on coronary artery disease (CAD) have not been reported. We investigated the effects of smoking status and the ALDH2 genotype, and assessed their interactive and combined effects on the risk of myocardial infarction (MI) or stable angina (SA), including 221 MI and 175 SA subjects and 473 age- and sex-matched controls without CAD. Current-smoking and the ALDH2*2 allele additively increased the risk of MI (adjusted odds ratio 4.54, 95% confidence interval 2.25-9.15), although this combination was not associated with the risk of SA. This combination also increased the peak creatine kinase (CK) level synergistically in the acute MI (AMI) subjects. Moreover, current-smoking was found to be a significant risk factor for an increased peak CK level in the ALDH2*2 allele carriers (B 2220.2IU/L, p=0.008), but not the non-carriers. Additionally, a synergistic effect of this combination on the triglycerides levels was also found in the AMI subjects. These preliminary findings suggest that the combination of current-smoking and the inactive ALDH2*2 allele may increase the risk of MI additively and the infarct size synergistically.

Impact of esomeprazole on platelet reactivity and clinical outcome according to CYP2C19 genotype in coronary heart disease patients during dual antiplatelet therapy.

OBJECTIVES: The aim of this study was to investigate the effect of CYP2C19 polymorphism and co-therapy with esomeprazole on the antiplatelet efficacy of clopidogrel. BACKGROUND: The antiplatelet efficacy of clopidogrel depends on CYP2C19 polymorphism or the co-administration of some kind of proton pump inhibitor (PPI). METHODS: CYP2C19 genotype and the residual platelet reactivity (RPR) were measured in 361 coronary heart disease patients (male, mean age 69yrs), and the risk of cardiovascular events over a 3-month follow-up was assessed to evaluate the impact of co-administration of esomeprazole during dual antiplatelet therapy with aspirin and clopidogrel. RESULTS: The values of RPR did not differ between esomeprazole and non-esomeprazole groups (4389 ± 1112 versus 4079 ± 1355 AU·min, P=0.103). RPR value was higher in intermediate metabolizers (IM) than in extensive metabolizers (EM) (4089 ± 1252 versus 3697 ± 1215 AU·min P=0.012) and, similarly, higher in poor metabolizers (PM) than in IM (4884 ± 1027 versus 4089 ± 1252 AU·min, P<0.001). There were no differences in RPR between esomeprazole and non-esomeprazole groups according to CYP2C19 genotype (EM, 3954 ± 1192 versus 3645 ± 1220 AU·min, P=0.361; IM, 4401 ± 1063 versus 4051 ± 1271 AU·min, P=0.293; PM, 4917 ± 669 versus 4876 ± 1099 AU·min, P=0.907, respectively). There was also no difference in clinical outcomes between esomeprazole and non-esomeprazole groups in the three-month follow-up (0% versus 0.92%, P=0.487). CONCLUSIONS: These results suggest that concomitant use of esomeprazole with clopidogrel is not associated with reduced antiplatelet efficacy of clopidogrel or increased risk of cardiovascular events, irrespective of CYP2C19 genotype.

Chronic kidney disease status modifies the association of CYP2C19 polymorphism in predicting clinical outcomes following coronary stent implantation.

INTRODUCTION: There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients with dual antiplatelet therapy. Chronic kidney disease (CKD) is associated with increased risk of cardiovascular event, but the association between the possession of CYP2C19 loss-of-function (LOF) alleles and clinical outcome according to the presence of CKD is poorly understood. The aim of this study was to investigate whether CKD status modifies the association of CYP2C19 polymorphism in predicting outcomes in a prospective cohort study. MATERIAL AND METHODS: We enrolled 331 patients following coronary stent implantation. Patients were divided into two groups: CKD (n=154) and non-CKD (n=177). Platelet reactivity and CYP2C19 polymorphism were examined. The subjects were further divided into two groups according to the possession of CYP2C19 LOF alleles: carriers and non-carriers. Patients were followed up and clinical events were evaluated according to CKD and carrier status. RESULTS: The proportion of high platelet reactivity was significantly higher in carriers than in non-carriers in both CKD (42.4% versus 21.7%; P=0.016) and non-CKD groups (34.3% versus 3.7%; P<0.001). In the non-CKD group alone, the incidence of cardiovascular events was significantly higher in carriers than in non-carriers (13.7% versus 1.7%; P=0.013). Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers than in non-carriers in the non-CKD group (log-rank test: P=0.013) and there was no significant difference in the CKD group (log-rank test: P=0.591). Multivariate analysis identified carriers as an independent predictor of cardiovascular events only in the non-CKD group alone (hazard ratio: 8.048; 95% confidence interval: 1.066 to 60.757; P=0.043). CONCLUSIONS: CYP2C19 polymorphism significantly correlates with clinical outcome in non-CKD patients, and CKD status modifies the association of CYP2C19 polymorphism in predicting clinical outcomes following coronary stent implantation.