细胞色素P450 2C19*2基因多态性联合钙通道阻滞剂与冠状动脉支架内血栓形成的相关性

目的:探讨经皮冠状动脉介入术(PCI)后接受氯吡格雷治疗的患者中,细胞色素P450 2C19(CYP2C19)*2基因多态性(681A)与支架内血栓形成的相关性,以及服用钙通道阻滞剂(CCBs)与支架内血栓形成的相关性。方法:检测1 738例冠心病PCI术后患者的CYP2C19基因多态性,并将这些患者分为CCBs组和非CCBs组,采用比浊法检测二磷酸腺苷(ADP)途径诱导的血小板最大聚集率(MPAR),比较两组患者MPAR及支架内血栓形成率的差异。结果:19例(2.4%)CYP2C19*2基因型的患者(包括CYP2C19*2/*2或*1/*2)和7例(0.75%)基因型为CYP2C19*1/*1的患者发生了明确的支架内血栓形成;CYP2C19*2基因型患者支架内血栓形成的发生率明显高于CYP2C19野生型纯合子患者(CYP2C19*1/*1)(风险比为4.26,95%可信区间为1.28～9.22,P<0.05);基因型为CYP2C19*1/*1的患者发生支架内血栓形成的风险最低,而基因型为CYP2C19*2/*2的患者支架内血栓形成的风险最高(风险比为0.568,95%可信区间为0.308～2.070,P<0.01);CCBs组和非CCBs组MPAR及支架内血栓形成率差异无统计学意义。结论:PCI术后接受氯吡格雷治疗的冠心病患者中,CYP2C19*2基因型患者支架内血栓形成的风险增加,而服用CCBs不会导致氯吡格雷抗血小板聚集作用减弱以及支架内血栓形成事件增加。     

The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy

Both high platelet reactivity (HPR) and CYP2C19 genotyping have been proposed to stratify cardiovascular event risk and to personalize maintenance dual antiplatelet therapy (DAPT) in stented patients. However, how well CYP2C19 genotype correlates with HPR in patients on maintenance DAPT is less clear. We determined the association of CYP2C19 loss-of-function (*2) and gain-of-function (*17) allele status with platelet reactivity in 118 stented patients on DAPT ≥2 weeks and in 143 patients with stable coronary artery disease on aspirin therapy alone. Thirty-three percent and 39% carried at least 1 copy of *2 and *17 alleles, respectively. Neither allele was associated with platelet reactivity in patients on aspirin therapy alone. On DAPT, platelet aggregation was higher in those with *2 allele than noncarriers (P ≤ .01) but did not differ between those with the *17 allele and noncarriers. The prevalence of HPR using the 20 μM adenosine diphosphate-induced aggregation cutpoint was 34% in the total population: 26% in *1/*1 homozygotes, 49% in those with the *2 allele, and 20% in those with the *17 allele (P = .006). Determination of diplotype status enhanced identification of HPR. However, platelet function on DAPT is highly variable within diplotype groups. Therefore, CYP2C19 genotype and HPR are imperfect correlates of each other. Because both predict cardiovascular events with similar risk ratios, CYP2C19 genotyping and HPR may provide complementary information to stratify risk and personalized DAPT in stented patients than either alone.     

细胞色素P4502 C19快代谢基因型缺血性卒中患者氯吡格雷抵抗的影响因素分析

目的 探讨细胞色素P4502C19(CYP2C19)快代谢基因型缺血性卒中患者氯吡格雷抵抗的影响因素.方法 回顾性连续纳入CYP2C19快代谢基因型(CYP2C19*1/*1)缺血性卒中住院患者204例,均于确诊后连续服用氯吡格雷75 mg/d,共7 d,第8天晨起空腹抽取静脉血,2 h内完成血栓弹力图血小板图的检测....     

Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome

The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The benefit of tailored therapy according to platelet function test results remains unclear, and the potential effect of genotypes on this benefit has not been addressed in unstable patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. Three hundred forty-six consecutive patients were enrolled and received a loading dose of 600 mg, including 86 *2 carriers (13 homozygotes and 73 heterozygotes) and 260 *2 noncarriers. Clopidogrel response, assessed with platelet reactivity index vasoactive-stimulated phosphoprotein, was significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C19*2 allele carriers (53% vs 41%, p = 0.04). All clopidogrel nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg clopidogrel maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame clopidogrel low response in only 44% of the whole population and significantly less frequently in *2 carriers than in noncarriers (28% vs 50%, p = 0.01). In conclusion, higher clopidogrel maintenance doses were able to overcome clopidogrel low response in fewer than half of clopidogrel low responders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. The benefit of this tailored therapy was significantly reduced in CYP2C19*2 carriers. Therefore, these patients might require alternative strategies with new P2Y?? blockers.     

Evaluation of the INNOVANCE PFA P2Y assay and its association with CYP2C19 genotypes

The purpose of this study was to evaluate associations between INNOVANCE PFA P2Y (PFA P2Y) test results and CYP2C19 genotypes and provide baseline data for PFA P2Y testing to establish a therapeutic monitoring strategy for clopidogrel. A total of 75 new patients with acute coronary syndrome with planned percutaneous coronary intervention were enrolled between June 2012 and September 2012. All patients received clopidogrel at an initial loading dose of 600?mg followed by a 75-mg daily maintenance dose. Blood samples were obtained on the third morning after clopidogrel loading. PFA P2Y, VerifyNow P2Y12 and VASP assays were used to determine platelet inhibition due to clopidogrel, and the Verigene CYP2C19 test was used for CYP2C19 genotyping. The genotype frequency of 75 patients was as follows: CYP2C19 *1/*1 (wild type), 28 (37.3%); *1/*2, 31 (41.3%); *1/*3, 4 (5.3%); *2/*2, 5 (6.7%); *2/*3, 5 (6.7%); *1/*17, 1 (1.3%); and *2/*17, 1 (1.3%). Classified according to CYP2C19 genotypes, there were 29 (38.7%) extensive metabolizers (EM) or ultra rapid metabolizers (UM), 35 (46.7%) intermediate metabolizers (IM), and 10 (13.3%) poor metabolizers (PM). Median (interquartile range) PFA P2Y closure times (seconds) were 119 (101–260), 300 (130–300) and 300 (300–300) in the PM, IM and EM or UM groups, respectively (p?<?0.05). Median (interquartile range) VerifyNow PRUs were 294 (213–297), 215 (165–320) and 189 (118–279); and the VASP platelet reactivity index (%) was 52.7 (33.3–91.9), 59.9 (41.4–72.8) and 38.9 (26.8–62.2) in the PM, IM and EM or UM groups, respectively (p?>?0.05). Compared with non-carriers, carriers of reduced function CYP2C19 alleles tended to have higher platelet reactivity after clopidogrel treatment. The cut-off for PM versus other groups (IM and EM or UM) was ≤141 seconds (AUC 0.704, sensitivity 70%, specificity 76.6%) on the ROC curve. A statistically significant correlation between PFA P2Y (seconds) and VerifyNow (PRU) was found (ρ?=??0.47, p?<?0.0001). In conclusion, the PFA P2Y test showed a statistically significant association with CYP2C19 metabolizer phenotypes based on CYP2C19 genotyping and effectively determined the risk groups resistant to clopidogrel therapy, including PM.     

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males

AIM：To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma （ESCC） in a high risk area of Gansu Province, in Chinese males.
METHODS： A case-control study was conducted to investigate the genetic polymorphisms of these enzymes （CYP2E1 ＊c1/＊c2, ALDH2 ＊1/＊2 and ADH1B ＊1/＊1 genotypes）. A total of 80 esophageal cancer cases and 480 controls were recruited.
RESULTS： Compared with controls, cases had a greater prevalence of heavier alcohol consumption （53.8% vs 16.2%） and a higher proportion of alcohol drinkers with 〉 30 drink-years （28.8% vs 13.5%）. Heavier alcohol consumption and alcohol drinking with 〉 30 drink- years increased the risk of ESCC, with ORs （95% CI） of 3.20 （1.32-9.65） and 1.68 （0.96-3.21）. CYP2E1 （＊c1/＊c1）, ALDH2 （＊1/＊2） and ADH1B （＊1/＊1） genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance （P = 0.014; P = 0.094; P = 0.0001 respectively）. There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 ＊1/＊2 as well as ADH1B encoded by ADH1B ＊1/＊1 and CYP2E1 encoded by CYP2E1 ＊c1/＊c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 （＊1/＊1 genotype） as well as ADH1B （＊1/＊2 ＋ ＊2/＊2） and CYP2E1 （＊c1/＊c2 ＋ ＊c2/＊c2） genotypes, with a statistically significant difference; ORs （95% CI） of 8.58 （3.28-22.68）, 27.12 （8.52-70.19） and 7.64 （2.82-11.31） respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 （＊1/＊2） combined the ADH1B （＊1/＊1） genotype or ALDH2 （＊1/＊2） combined the CYP2E1 （＊c1/＊c1） genotype leads to synergistic interactions, higher than drinkers with ALDH2 （＊1/＊1） ＋ ADH1B （＊1/＊2 ＋ ＊2/＊     

Factors determining clinical effectiveness of clopidogrel and prognosis of patients with stable ischemic heart disease

Aim of the study was to elucidate genetic and drug factors affecting efficacy of clopidogrel in patients with ischemic heart disease - inhabitants of central region of Russian Federation. We included 399 patients with IHD (79% men, mean age 58.3+/-9 years) receiving long term therapy with clopidogrel 75 mg/day (during stable manifestations of the disease) or 75-150 mg/day in combination with aspirin (in relation with recent elective percutaneous interventions). We studied carriage of polymorphisms of genes controlling intestinal absorption of clopidogrel (ABCB1 C3435T), activation of clopidogrel in the liver (CYP2C19 *1 *2), and also registered concomitant administration of proton pump inhibitors (PPI). Then we determined relationship of these factors to development of vascular complications (vascular death/myocardial infarction/requirement in revascularization) during 18 months followup. Among studied genetic factors carriage of allele variants CYP2C19 *1/*2 and *2/* (found in 25.5 and 1.8% of patients, respectively), possessed prognostic significance. In the group of clopidogrel monotherapy carriage of at least one *2 allele was associated with increased rate of vascular complications (33.3% vs. 11.3%) including thrombotic complications (27.7% vs. 3.2%; =0.01). In patients receiving 75 mg/day of clopidogrel in combination with aspirin total rate of thrombotic complications as well as of all adverse unfavorable outcomes was higher in *2 carriers compared with wild type homozygotes (14.0% vs.8.7% and 21.0% vs. 15.8%, respectively). In patients receiving double dose clopidogrel in combination with aspirin we found no worsening of outcomes associated with CYP2C19*2 carriage. In the multifactorial risk model independent predictors of vascular complications turned out to be CYP2C19 *2/*2 homozygosity (RR 4.9; =0.02) and concomitant PPI administration ( 1.8; p=0.05).     

细胞色素P4502C19基因多态性对介入术后服用氯吡格雷冠心病患者临床预后的影响

目的 探讨细胞色素P450(CYP)2C19 681G>A基因多态性对经皮冠状动脉介入治疗(PCI)后服用氯吡格雷冠心病患者临床预后的影响.方法 入选2009年1月1日至8月31日拟行PCI,并在术后服用氯吡格雷12个月的冠心病患者267例.采用MassARRAY时间飞行质谱检测入选患者CYP2C19 681G>A位点.按基因型不同,将患者分为CYP2C19*1/*1组 (n=130)和CYP2C19*2携带组(n=137).观察两组患者术后1年心绞痛复发、紧急血运重建术、急性心肌梗死、支架内血栓形成和死亡的发生情况.结果 两组患者的临床基本资料差异无统计学意义(P>0.05).PCI术后1年,CYP2C19*2携带组紧急血运重建术和联合终点事件的发生率均高于CYP2C19*1/*1组 (分别为7.3%比1.5%和8.0%比2.3%,P均<0.05).两组患者心绞痛复发、急性心肌梗死、支架内血栓形成和死亡的发生率差异均无统计学意义(P均>0.05).CYP2C19*2携带组随访1年的累积联合终点事件发生风险是CYP2C19*1/*1组的3.59倍(HR=3.59,95%CI:1.02～12.87,P<0.05).结论 CYP2C19 681G>A基因多态性可能是影响PCI术后服用氯吡格雷冠心病患者临床预后的因素.

Abstract：

Objective To investigate the impact of cytochrome P450 (CYP) 2C19 681G>A polymorphism on long-term prognosis of clopidogrel-treated Chinese patients after percutaneous coronary intervention (PCI).Methods Between January 1, 2009 and August 31,2009, 267 patients with coronary heart disease who received PCI and treated with clopidogrel for 12 months were enrolled. CYP2C19*2 was detected by MALDI-TOF MS and patients were grouped into CYP2C19*1/*1(n=130) and CYP2C19*2 carriers group (n=137). Follow-up was 12 months. The primary endpoint was angina recurrence, urgent coronary revascularization, acute myocardial infarction, stent thrombosis, death and the combined end points. Results Baseline data were similar between two groups (P>0.05).Urgent coronary revascularization and the combined end points occurred more frequently in CYP2C19*2 carriers than in CYP2C19*1/*1 patients (7.3% vs. 1.5% and 8.0% vs. 2.3% respectively,all P<0.05). But incidence of angina recurrence, acute myocardial infarction, stent thrombosis and death was similar between two groups (all P>0.05).Hazard risk of 1 year cumulative survival of CYP2C19*2 carriers group was significantly higher than CYP2C19*1/*1 group after PCI (HR=3.59, 95%CI: 1.02-12.87, P<0.05). Conclusion CYP2C19 681G>A polymorphism is a determinant of prognosis in coronary heart disease patients receiving chronic clopidogrel treatment after PCI.     

CYP 450 2C19 polymorphisms in Indian patients with coronary artery disease

Background

Dual antiplatelet therapy is the cornerstone in the management of acute coronary syndromes (ACS) and prevention of stent thrombosis (ST). Genetic polymorphisms in CYP2C19 gene involved in hepatic activation of clopidogrel leads to clopidogrel non-responsiveness and may influence clinical outcomes. These polymorphisms in CYP2C19 gene and their impact on clinical outcome in coronary artery disease (CAD) have not been studied in Indian population.

Methods

We studied 110 consecutive patients (mean age 55.7 ± 10.7 years; 90% male) taking clopidogrel with angiographically proven CAD for various genetic polymorphisms in CYP2C19 gene. Relationship between loss of function mutation and clinical presentation with recurrent ACS including ST was analyzed.

Results

Out of 110 patients, 26 (23.64%) had normal genotype, 52 (47.23%) had loss of function mutation *2 and 39 (35.45%) had a gain of function mutation *17, 7 (6.36%) patients were undefined metabolizers (*2/*17) which were excluded from analyses. Final analyses included 103 patients, with 45 (40.90%) having loss of function. Overall 51 patients had ACS, with 27 developing recurrence while on clopidogrel. The prevalence of loss of function mutation was no different between the group with recurrences and those without recurrences (55.6% vs. 50%, p = 0.7). Two patients developed ST while on clopidogrel; both had loss of function mutation.

Conclusion

CYP2C19 gene polymorphisms are common in Indian population. Loss of function mutation status did not affect the clinical outcomes. A larger study also considering P2Y12 receptor polymorphisms together with platelet activity testing, may be required to establish the role of CYP2C19 gene polymorphisms in clinical practice.     

Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome

Genetic polymorphisms of cytochrome P450 (CYP) isoforms may promote variability in platelet response to clopidogrel. This study was conducted to analyze, in 603 patients with non-ST elevation acute coronary syndromes, the effect of CYP3A4, CYP3A5, and CYP2C19 gene polymorphisms on clopidogrel response and post-treatment platelet reactivity assessed by adenosine diphosphate (ADP)-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression. The CYP2C19*2 polymorphism was significantly associated with ADP-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression in recessive (p <0.01, p <0.007, and p <0.06, respectively) and codominant (p <0.08, p <0.0001, and p <0.009, respectively) models, but the CYP3A4*1B and CYP3A5*3 polymorphisms were not. The CYP2C19*2 allele carriers exhibited the highest platelet index levels in multivariate analysis (p = 0.03). After covariate adjustment, the CYP2C19*2 allele was more frequent in clopidogrel nonresponders, defined by persistent high post-treatment platelet reactivity (ADP-induced platelet aggregation >70%; p = 0.03). In conclusion, the present data suggest that the CYPC19*2 allele influences post-treatment platelet reactivity and clopidogrel response in patients with non-ST elevation acute coronary syndromes.     

稳心颗粒对心房颤动患者射频消融术后早期复发的影响

目的 探讨中国西北地区汉族部分冠心病患者CYP2C19基因型分布特点,依据基因检测指导PCI术后氯吡格雷抗血小板治疗。方法 ①入选2013年1月~7月在西京医院心内科诊断冠心病患者且行基因型检测共2 117例,根据不同等位基因功能缺失分为快代谢基因型（*1/*1）;中间代谢型 CYP2C19（*1/*2）、（*1/*3）;慢代谢型CYP2C19（*2/*2）、（*2/*3）、（*3/*3）;②选择上述临床资料完整的急性冠脉综合征（ACS）患者共864例,于术后1,3,6,9和12个月随访两组间主要不良心血管事件(MACE)发生情况。结果 ①检测入选的2 117例患者基因型结果显示,快代谢型885例,发生率41.80%,中间代谢型971例,发生率45.86%,慢代谢型261例,发生率12.32%;对入组患者一般临床资料统计分析,各组基因型在性别、不同地区、不同年龄分布的比较均存在差异,具有统计学意义。②快代谢型（正常代谢组）患者346例,中间代谢和慢代谢型（弱代谢组）患者461例,记录随访结果两组间MACE发生率比为〔7.8%（27/346） vs. 5.4%（25/461）〕,两组间无统计学差异。结论 ①入选患者基因型突变以*1/*2为主,各组在性别、地区、年龄组分布的比较均存在差异;②按患者CYP2C19基因型调整氯吡格雷用量进行抗血小板治疗是有效的。     

Inhibition of platelet aggregation by prostaglandin E1 (PGE1) in diabetic patients during therapy with clopidogrel and aspirin

Diabetes mellitus (DM) is associated with increased platelet activation and reduced platelet inhibition by clopidogrel. Prostaglandin E1 (PGE1) stimulates adenyl cyclase activity in platelets and increases cyclic AMP concentrations, which inhibit Ca²⁺release and platelet aggregation induced by P2Y1 receptor activation. PGE1 is included in the VerifyNow P2Y12 assay to suppress P2Y1 induced platelet aggregation. We hypothesized that diabetes mellitus may be associated with altered response to PGE1 in subjects treated with clopidogrel. Subjects with established coronary artery disease who were taking clopidogrel 75?mg daily and aspirin for >14 days were enrolled (n?=?96). Diabetic (n?=?34) were compared with non-diabetic subjects (n?=?62). VerifyNow P2Y12 assay and light transmittance aggregometry (LTA) were performed using ADP as agonist with and without addition of PGE1. Genomic DNA was genotyped for common cytochrome P450 (CYP) 2C19 variants using Taqman assays. Residual on-treatment platelet aggregation induced by 20?µM ADP was not significantly different between subjects with and without DM. Addition of 22?nM and 88?nM PGE1 to 20?µM ADP resulted in a significant reduction of maximal platelet aggregation (MPA). Residual LTA platelet aggregation with PGE1 and VerifyNow P2Y12 platelet reactivity were significantly higher in subjects with DM than those without DM and in carriers of CYP 2C19*2 polymorphism. We conclude that an impaired inhibitory response to PGE1 may contribute to the high platelet reactivity phenotype in subjects with DM treated with clopidogrel. Addition of PGE1 to ADP agonist platelet assays may identify subjects with blunted inhibitory response to prostaglandins and result in a higher proportion of subjects with DM being classified as non-responders.     

CYP2C19*2 and prognosis after an acute coronary syndrome: Insights from a Portuguese center

BackgroundClopidogrel requires oxidation dependent on the cytochrome P450 enzyme 2C19 (CYP2C19) to form its active metabolite. The importance of loss-of-function alleles (particularly CYP2C19*2, 681G>A) in poor platelet response to clopidogrel is well recognized.ObjectiveTo investigate the prevalence and prognostic impact of the CYP2C19*2 allele in a local acute coronary syndrome (ACS) population.MethodsWe performed a prospective, longitudinal study of 95 patients admitted for an ACS between March and October 2009 to a single coronary care unit. Patients aged under 75 who survived hospital stay and for whom clopidogrel was prescribed were included. At discharge, CYP2C19 was genotyped using a commercially available kit. Patients were divided into two groups: Group A (non-carriers, normal metabolizers, CYP2C19*1/*1), n = 69; and Group B (carriers, slow metabolizers, CYP2C19*2/*1 or *2/*2), n = 26. The primary endpoint was a combined outcome of cardiovascular death, non-fatal myocardial infarction or re-admission for unstable angina; median follow-up was 136.0 (79.0–188.0) days.ResultsThe median age of the population was 62.0 (51.0–68.0) years, and 83.2% were male. The CYP2C19*2 (A) allele had a frequency of 14.2%. There were no differences between the groups with respect to demographic data or history of cardiovascular disease. Coronary anatomy, left ventricular ejection fraction and renal function were also similar. The groups were also homogenous with respect to GRACE risk score (118.0 (95.0–136.5) vs. 115.0 (96.0–133.0), p = 0.68), medical treatment and percutaneous revascularization during hospital stay. Event-free survival was higher for Group A (94.0% vs. 75.0%, log-rank p = 0.010). Three readmissions for MI were documented, all in the slow metabolizers group.ConclusionIn our ACS population, the CYP2C19*2 allele was a medium-term prognostic marker.     

非瓣膜病房颤与CYP2C9基因多态性的相关性研究

目的：就汉族非瓣膜病房颤与CYP2C9基因多态性进行相关性研究;方法：自2017 年 09月至2019 年 3 月收集来自于山西省不同地区就诊于山西医科大学第二医院心内科的汉族患者,本研究共纳入256例患者,男134例,女122例,将入选对象分为非瓣膜病房颤组143例,对照组113例,所有入选研究对象均无血缘关系;分别对入选对象进行CYP2C9基因型检测,分析基因型与等位基因在两组间有无差异。结果：非瓣膜病房颤组CYP2C9*1/*3 基因型分布频率高于对照组,其中非瓣膜病房颤组为CYP2C9*1/*3 基因型的患者占19例,对照组为CYP2C9*1/*3 基因型的患者仅6例,差异有统计学意义（P=0.035）;非瓣膜病房颤组CYP2C9*3 等位基因分布频率高于对照组,其中非瓣膜病房颤组CYP2C9*3 等位基因19个,对照组CYP2C9*3 等位基因6个,差异有统计学意义（P=0.040）。二元Logistic回归结果示：排除年龄、低密度脂蛋白、高血压等因素的影响后,携带有CYP2C9*1/*3基因型的研究对象患非瓣膜病房颤的风险增加 (OR=2.637, 95%CI=0.989~7.026)。结论：CYP2C9基因多态性是汉族非瓣膜病房颤发生的危险因素。     

High on-treatment platelet reactivity by ADP and increased risk of MACE in good clopidogrel metabolizers

High on-treatment platelet reactivity (HPR) by ADP, which primarily reflects the effect of thienopyridines, has been found to be an independent predictor of ischemic events in patients with acute coronary syndrome (ACS) on dual antiplatelet therapy. CYP2C19*2 is associated with HPR by ADP. The aim of our study was to evaluate if high on-clopidogrel platelet reactivity (HPR) by ADP is associated with an increased risk of major adverse coronary events (MACE) after ACS independent of CYP2C19*2 allele, i.e. whether genotyping patients for CYP2C19*2 polymorphism is sufficient to identify those to be switched to novel antiplatelets. A total of 1187 patients were included (CYP2C19 *1/*1 n?=?892; *1/*2 n?=?264; *2/*2 n?=?31); 76 MACE (CV death and non-fatal MI) were recorded in non-carriers of CYP2C19*2 (8.5%) and 39 in carriers of CYP2C19*2 (13.2%). At the landmark analysis in the first 6 months, HPR by ADP and CYP2C19*2 allele were both significantly and independently associated with MACE [HPR by ADP: HR?=?2.0 (95% CI 1.2–3.4), p?=?0.01; CYP2C19*2 allele: HR?=?2.3 (95% CI 1.3–3.9), p?=?0.003]. At the land mark analysis from 7 to 12 months, only HPR by ADP remained significantly associated with the risk of MACE [HPR by ADP: HR?=?2.7 (95% CI 1.4–5.3), p?=?0.003; CYP2C19*2: HR?=?0.8 (95% CI 0.2–1.1), p?=?ns]. CYP2C19*2 allele and HPR by ADP are both independently associated with an increased risk of MACE in the first 6 months after ACS. HPR by ADP is associated with an increased risk until 12 months of follow-up. Therefore, both phenotype and genotype are clinically relevant for the evaluation of the antiplatelet effect of clopidogrel and for the prognostic stratification of ACS patients.     

Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen

Introduction: Warfarin is one of the most widely used anticoagulants, yet interindividual differences in drug response, a narrow therapeutic range and a high risk of bleeding or stroke complicate its use. We aimed to determine the allele and genotype frequency of VKORC1 1173 C>T, CYP2C9*2 and CYP2C9*3 variant polymorphisms in the Egyptian population and to evaluate their influence on the interindividual differences in warfarin dosage. Methods: A total of 154 unrelated healthy adult patients and 46 warfarin-treated patients were included. SYBR Green-based real-time polymerase chain reaction (PCR) assay was used for studying VKORC1 (C1173T) and CYP2C9*3 polymorphisms. Mutagenically separated PCR assay was used to detect the CYP2C9*2 allele. Results: VKORC1 genotype frequencies were 11%, 24% and 65% for CC, CT and TT, respectively. The prevalence of CYP2C9 haplotypes was 81% (*1\*1), 3.3% (*1\*2), 9.7% (*1\*3), 4.5% (*2\*2) and 0.65% (2\*3 and *3\*3). VKORC1 TT and CYP2C9*2\*2 were associated with a significantly lower warfarin dose. VKORC1 and CYP2C9 accounted for 31.7% and 15.6% of warfarin dose variability, respectively, and together with clinical factors explained 61.3% of total variability. Conclusion: VKORC1-TT and CYP2C9 *1/*1 are the most prevalent genotypes among Egyptians. Patients with VKORC1-TT genotype required a lower warfarin dose.     

Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection.

BACKGROUND & AIMS: The relationship between single nucleotide polymorphisms (SNPs) and clinical outcomes has been intensively studied. We intended to determine SNPs of CYP2C19 and 23S rRNA of Helicobacter pylori by using rapid urease test (RUT)-positive gastric mucosal samples. METHODS: One hundred thirty-nine patients with H pylori -positive results based on RUT completed 1-week treatment with lansoprazole 30 mg twice a day, clarithromycin 200 mg 3 times daily, and amoxicillin 500 mg 3 times daily. SNPs from adenine to guanine at positions 2142 and 2143 of 23S rRNA of H pylori (A2142G and A2143G) and SNPs from guanine to adenine at positions 681 in exon 5 (* 2 ) and 636 in exon 4 (* 3 ) of CYP2C19 were determined by the serial invasive signal amplification reaction assay by using DNAs extracted from gastric tissue samples already used for RUT. Minimum inhibitory concentrations of clarithromycin for H pylori were determined by culture test. CYP2C19 genotypes were classified into the rapid metabolizer (* 1 /* 1 ), intermediate metabolizer (* 1 /* 2 or * 1 /* 3 ), and poor metabolizer (* 2 /* 2 , * 2 /* 3 , or * 3 /* 3 ) groups. RESULTS: H pylori strains with A2142G or A2143G mutation had higher minimum inhibitory concentrations for clarithromycin. Cure rates in rapid, intermediate, and poor metabolizer groups were 57.8% (95% confidence interval, 42.1%-72.4%), 88.2% (78.1%-94.8%), and 92.3% (74.9%-99.1%), respectively ( P < .001). Cure rates in strains with and without A2142G or A2143G mutation were 48.3% (29.4%-67.5%) and 87.3% (79.5%-92.7%), respectively ( P < .001). CONCLUSIONS: SNPs of CYP2C19 and 23S rRNA of H pylori using RUT-positive gastric mucosal samples could be predictable determinants for H pylori eradication by triple therapy.     

Polymorphisms of MDR1, CYP2C19 and P2Y12 genes in Indian population: Effects on clopidogrel response

Aims/objectiveInfluence of genetic variations on the response of clopidogrel, an antiplatelet drug is implicated. In the present study, the prevalence of single nucleotide polymorphisms of MDR1 (C3435T), CYP2C19 [CYP2C19*2 CYP2C19*3, CYP2C19*17] and P2Y₁₂ (i-T744C) in Indian population and their effects on clopidogrel response was analyzed.Methods and resultsTo analyze the prevalence of polymorphisms, 102 healthy individuals were recruited. Clopidogrel response was assessed by ADP induced platelet aggregation in clopidogrel naïve acute myocardial infarction (AMI) patients (n = 26) screened from 100 AMI cases, before loading dose of 300 mg, at 24 h before next dose and 6 days after on 75 mg per day and platelet aggregation inhibition (PAI) was calculated between these time intervals. Genotyping was carried out by PCR-based restriction enzyme digestion method for C3435T of MDR1 and i-T744C of P2Y₁₂, by multiplex PCR for CYP2C19*2 (G681A) and CYP2C19*3 (G636A) and by nested PCR for CYP2C19*17 (C806T). The effect of the above mentioned genetic variations on PAI was analyzed. Variant allele of CYP2C19*3 was not observed while the prevalence of 3435T of MDR1 (0.524), CYP2C19*2 (681A, 0.352); i-744C of P2Y₁₂ (0.088), as well as wild type allele CYP2C19*17 (C806, 0.897) associated with decrease clopidogrel response were observed. Trend toward poor response to clopidogrel was observed at 24 h with the variant genotypes of CYP2C19*2 and i-T744C of P2Y₁₂ as compared to wild type.ConclusionThe present study did show a trend toward impaired response of clopidogrel to inhibit platelet aggregation with variant genotypes of CYP2C19*2 and iT744C of P2Y₁₂ compared to respective wild type genotype at 24 h.     

Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study

Aims CYP3A4-metabolized statins can influence the pharmacodynamic effect of clopidogrel. We sought to assess the impact of switching to a non-CYP3A4-metabolized statin on platelet function among patients receiving clopidogrel and atorvastatin with high on-treatment platelet reactivity (HPR). Methods and results Percutaneous coronary intervention (PCI)-treated patients (n= 50) with HPR [20 μM adenosine diphosphate (ADP)-induced maximal platelet aggregation (MPA) >50%] were enrolled during chronic administration of atorvastatin (10 mg/day) and clopidogrel (75 mg/day) (≥6 months). They were randomly assigned to a 15-day therapy with either rosuvastatin 10 mg/day (n= 25) or pravastatin 20 mg/day (n= 25). Platelet function was assessed before and after switching by conventional aggregometry and the VerifyNow P2Y12 assay. Genotyping was performed for CYP2C19*2/*3, CYP3A5*3, and ABCB1 C3435T alleles. The primary endpoint was the absolute change in 20 μM ADP-induced MPA. After switching, MPAs after stimuli with 20 and 5 μM ADP were decreased by 6.6% (95% confidence interval: 3.2-10.1%; P < 0.001), and 6.3% (95% confidence interval: 2.5-10.2%; P = 0.002), respectively. Fifty-two P2Y12 reaction units fell (95% confidence interval: 35-70; P < 0.001) and the prevalence of HPR decreased (24%; P < 0.001). Pharmacodynamic effects were similar after rosuvastatin and pravastatin therapy. In addition to smoking status, the combination of calcium channel blocker usage and ABCB1 C3435T genotype significantly affected the change of 20 μM ADP-induced MPA. Conclusions Among PCI-treated patients with HPR during co-administration of clopidogrel and atorvastatin, switching to a non-CYP3A4-metabolized statin can significantly decrease platelet reactivity and the prevalence of HPR. This switching effect appears similar irrespective of the type of non-CYP3A4-metabolized statin.     

The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study

Aims Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. Methods and results A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. Conclusion No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. Clinical Trial Registration: This study is registered with ClinicalTrials.gov number, NCT00050817.