Impact Of Cyp2c19*2 Genotype On Antiplatelet Response To Clopidogrel And Active Metabolite Exposure In Chinese Patients

BackgroundIt has been reported that platelet inhibition by clopidogrel is highly variable, and patients with high on treatment platelet reactivity (OTPR) have increased risk for ischemic events.The CYP2C19*2 loss of function polymorphism has been reported to be associated with high OTPR. And we determined whether the CYP2C19*2 polymorphism is associated with OTPR in Chinese patients.MethodsOTPR was measured in 1084 consecutive patients receiving a 75mg dose for at least 5 days by using the 20?M ADP induced light transmitted aggregation method, and the CYP2C19*2 status was genotyped. We applied a cutoff value of 64.5% to define high OTPR.ResultsThe OTPR was significantly higher in CYP2C19*2 carriers (50.73±20.33 for CYP2C19*2 heterozygous and 54.00±20.90 for CYP2C 19*2 homozygous) compared with that of non-carriers (48.25±20.43 ). Carriage of CYP2C 19*2 risk allele was independently associated with higher risk of high OTPR (OR, 1.37; 95%CI, 1.11-1.69; p=0.003 for allele effect and OR, 1.38; 95%CI, 1.04-1.81; p=0.003 for carriage status).ConclusionsThe OTPR was significantly higher in CYP2C19*2 carriers compared with that of non-carriers. Carriage of CYP2C19*2 risk allele was independently associated with increased risk of high OTPR.BackgroundCarriers of the loss of function CYP2C19*2 genetic polymorphism convert less clopidogrel into its active metabolite, which results in reduced platelet inhibition and increased ischemic events. We aim to evaluate whether increasing the maintenance dose in CYP2C19*2 carriers overcomes the genetic defect of CYP2C19.MethodsWe allocated 5 patients of each CYP2C19*2 genotype to evaluate the impact of the risk allele on pharmacokinetic response to clopidogrel, and tested whether increasing clopidogrel maintenance doses increases active metabolite exposure.ResultsWith 75mg daily dose, the exposure levels of the active metabolite was lower in CYP2C19*2 heterozygous (73.5%) and homozygous (51.6%) patients compared with that observed in non-carriers. Switching from 75 mg daily clopidogrel to 150 mg daily increased the exposure levels to clopidogrel active metabolite in both CYP2C19*2 heterozygous (96.1% compared to non-carriers with 75mg daily dose) and homozygous(88.4% compared to non-carriers with 75mg daily dose).ConclusionsCarriers of the CYP2C19*2 genetic variant have lower levels of clopidogrel active metabolite exposure. And a dose escalation to 150mg daily clopidogrel may normalize active metabolite exposure in CYP2C19*2 carriers.Background The evidence that the variants GCK rs 1799884, GCKR rs780094, MTNR1B rs10830963 and G6PC2 rs560887, which are related to fasting plasma glucose levels,increase the risk of type 2 diabetes mellitus (T2DM) is contradictory. We therefore performed a meta-analysis to derive a more precise estimation of the association between these polymorphisms and T2DM.Methods All the publications examining the associations of these variants with risk of T2DM were retrieved from the MEDLINE and EMBASE databases. Using the data from the retrieved articles, we computed summary estimates of the associations of the four variants with T2DM risk. We also examined the studies for heterogeneity, as well as for bias of the publications.Results A total of 113,025 T2DM patients and 199,997 controls from 38 articles were included in the meta-analysis. Overall, the pooled results indicated that GCK (rsl799884),GCKR (rs780094) and MTNR1B (rs10830963) were significantly associated with T2DM susceptibility (OR, 1.04; 95%CI, 1.01-1.08; OR, 1.08; 95%CI, 1.05-1.12 and OR, 1.05;95%CI, 1.02-1.08, respectively). After stratification by ethnicity, significant associations for the GCK, MTNR1B and G6PC2 variants were detected only in Caucasians (OR, 1.09;95%CI, 1.02-1.16; OR, 1.10; 95%CI, 1.08-1.13 and OR, 0.97; 95%CI, 0.95-0.99,respectively), but not in Asians (OR, 1.02, 95% Cl 0.98-1.05; OR, 1.01; 95%CI, 0.98-1.04 and OR, 1.12; 95%CI, 0.91-1.32, respectively).Conclusions Our meta-analyses demonstrated that GCKR rs780094 variant confers high cross-ethnicity risk for the development of T2DM,while significant associations between GCK, MTNR1B and G6PC2 variants and T2DM risk are limited to Caucasians.