PCI术后患者PXR、CYP3A4和ABCB1基因多态性与氯吡格雷临床疗效的关联性分析

发布时间：2018-01-02 17:31

本文关键词：PCI术后患者PXR、CYP3A4和ABCB1基因多态性与氯吡格雷临床疗效的关联性分析　出处：《安徽医科大学》2016年硕士论文　论文类型：学位论文

【摘要】：目的考察PCI术后患者PXR、CYP3A4和ABCB1基因多态性与氯吡格雷临床疗效的关联。方法纳入自2014年6月到2015年9月在安徽省某三甲医院行PCI术的住院患者,所有患者均接受标准的双联抗血小板治疗方案(口服氯吡格雷负荷剂量300mg/d+维持剂量75mg/d,口服阿司匹林负荷剂量100mg/d+维持剂量1OOmg/d,术后至少服用12个月)。于氯吡格雷血药浓度稳态状态下,晨起空腹静脉采血5mL,分别测定氯吡格雷羧酸代谢物(CLPM)血药谷浓度、血小板最大聚集率(MAR),并采用Sequenom MassArray系统进行PXR、CYP3A4和ABCB1基因分型。通过再入院记录、门诊或电话随访患者术后12个月内终点事件发生情况。运用SPSS17.0统计软件和Haploview 4.2遗传分析软件研究基因多态性与氯吡格雷临床疗效的关联。结果1.共收集符合条件的患者384例,术后12个月内预后良好的患者共202例定义为正常组,发生不良心血管事件(MACE)的患者共153例定义为MACE组,出血事件的患者共29例定义为出血组。CLPM血药浓度：正常组 vsMACE组(0.573±0.355)μg/mL vs(0.346±0.142)1μg/mL,P0.05；正常组vs出血组(0.573±0.355)1μg/mLvs(1.669±0.280)μg/mL,P0.05;CLPM的临床有效参考值范围为0.172-1.3591μg/mL。MAR:正常组vsMACE组(34.79±10.76)%vs(59.90±7.15)%,P0.05；正常组vs出血组(34.79±10.76)%vs(20.10±7.50)%,P0.05；MAR的临床有效参考值范围为15.21%～59.54%。Pearson相关性分析显示CLPM血药浓度与MAR呈显著的负相关,相关系数为r=-0.850,P=0.000。Logistic回归分析显示冠脉病变血管数是MACE的危险因素。2.分析等位基因和基因型频率与终点事件关联：PXR rs3814057C:正常组vs MACE组0.460 vs 0.546,P=0.O243; PXR rs3814058 C:正常组vs MACE组0.460 vs 0.543,P=0.0293; PXR rs6785049 G:正常组vs MACE组0.532 vs 0.611,P=0.0356。显性模型条件下不同基因型患者MACE发生率的比较：PXR rs3814057 CC vs AA+AC, OR=1.795,95%CI (1.106-2.912), P=0.0171; PXR rs3814058 CC vs TT+CT,OR=1.808,95%CI(1.109-2.947),P=0.0168,具有统计学意义。以上结果提示,PXR rs3814057、PXR rs3814058和PXR rs6785049位点基因多态性与MACE显著相关,但与出血事件发生无显著相关性,且 CYP3A4、ABCB1及除上述3个位点之外的其他PXR SNPs等位基因和基因型频率与终点事件均无显著相关性。3.分析单体型频率与终点事件关联：PXR rs1523130、rs3814055、rs1523127、rs2276706四个位点连锁不平衡,共形成2种单体型为CCAG和TTCA, PXRrs6785049、rs3814057、rs3814058三个位点连锁不平衡,共形成3种单体型分别为GCC、AAT和GAT。其中单体型GCC频率分布：正常组vs MACE组0.458 vs 0.539,P=0.031；单体型AAT频率分布：正常组vs MACE组0.465 vs 0.382,P=0.027,具有统计学意义。结论1.本研究确定了CLPM的临床有效参考值范围为0.172～1.359μg/mL; MAR的临床有效参考值范围为15.21%～59.54%。今后,可通过实时监测CLPM浓度和MAR值来调整氯吡格雷的给药剂量。2.病变血管数、MAR及CLPM血药浓度与患者服用氯吡格雷后MACE的发生显著相关,其中病变血管数、MAR与MACE呈正相关,CLPM血药浓度与MACE呈负相关。3.MAR及CLPM血药浓度与患者服用氯吡格雷后出血事件的发生显著相关,其中MAR与出血事件呈负相关,CLPM血药浓度与出血事件呈正相关。4. CYP3A4 rs2242480 CT、rs35599367 GA和ABCB1 rs1128053 GA、rs2032582CA/T、rs1045642 GA与氯吡格雷临床疗效无显著相关性。5. PXR rs3814057 AC、PXRrs3814058TC和PXR rs6785049 AG与MACE显著相关,但与出血事件无明显关联,突变型纯合子患者MACE发生率显著高于野生型和突变型杂合子,PXR其他SNPs与氯吡格雷临床疗效无显著相关性。6. PXRrs6785049-rs3814057-rs3814058 GCC单体型和AAT单体型与MACE显著相关,GCC单体型患者MACE发生风险增加,AAT单体型患者MACE发生风险降低。
[Abstract]:Objective to investigate the PXR patients after PCI, CYP3A4 and ABCB1 related gene polymorphism and clinical efficacy of clopidogrel. Methods from June 2014 to September 2015 in hospitalized patients in a hospital in Anhui province underwent PCI surgery, all patients received dual antiplatelet therapy (standard oral clopidogrel loading dose 300mg/d+ dose 75mg/d, oral aspirin load dose 100mg/d+ dose 1OOmg/d, taking at least 12 months after surgery). In the steady-state plasma concentration of clopidogrel, fasting venous blood 5mL, clopidogrel carboxylic acid metabolites were measured (CLPM) blood trough concentration, platelet aggregation rate (MAR), and the Sequenom MassArray system of PXR, CYP3A4 and ABCB1 genes typing. Through re admission records, the occurrence of end point events within 12 months of outpatient or telephone follow-up after surgery. The use of SPSS17.0 statistical software and Hapl Association of oview 4.2 gene polymorphism genetic analysis software research and clinical efficacy of clopidogrel. Results 1. were collected from 384 Cases of eligible patients, a total of 202 cases defined within 12 months after surgery in patients with a good prognosis for the normal group, the occurrence of adverse cardiovascular events (MACE) a total of 153 cases of patients defined as group MACE, a total of 29 cases of bleeding events were defined bleeding blood drug concentration of group.CLPM: normal group vsMACE group (0.573 + 0.355) g/mL vs (0.346 + 0.142) 1 g/mL, P0.05; group vs normal bleeding group (0.573 + 0.355) 1 g/mLvs (1.669 + 0.280) g/mL, P0.05 CLPM; clinical efficacy the reference value range of 0.172-1.3591 g/mL.MAR: normal group and vsMACE group (34.79 + 10.76)%vs (59.90 + 7.15)%, P0.05 normal group; vs hemorrhage group (34.79 + 10.76)%vs (20.10 + 7.50)%, P0.05 MAR; the clinical effective reference value range is 15.21% ~ 59.54%.Pearson correlation analysis showed that serum concentrations of CLPM A significant negative correlation with MAR, correlation coefficient r=-0.850, P=0.000.Logistic regression analysis showed that the number of coronary artery stenosis is associated with risk factors for.2. analysis of allele and genotype frequency and end point events in MACE: PXR rs3814057C: normal group vs group MACE 0.460 vs 0.546 P=0.O243; PXR rs3814058 C: normal group vs group MACE 0.460 vs 0.543 P=0.0293; PXR rs6785049, G: normal group vs group MACE 0.532 vs 0.611, MACE P=0.0356. patients with different genotypes under the condition of the occurrence rate of the dominant model: PXR rs3814057 CC vs AA+AC comparison, OR=1.795,95%CI (1.106-2.912), P=0.0171 PXR rs3814058 CC vs; TT+CT, OR=1.808,95%CI (1.109-2.947), P=0.0168, was statistically significant. These results suggest that, PXR rs3814057, PXR rs3814058 and PXR were significantly related to rs6785049 gene polymorphism and MACE, but had no significant correlation with bleeding events, and CYP3A4, ABC In addition to the above 3 B1 and other PXR SNPs loci allele and genotype frequency and end point events were no significant correlation between.3. haplotype frequency analysis and end point event correlation: PXR rs1523130, rs3814055, rs1523127, rs2276706 of four loci in linkage disequilibrium, formed a total of 2 haplotypes were CCAG and TTCA, PXRrs6785049. Rs3814057 rs3814058, three loci in linkage disequilibrium, formed a total of 3 haplotypes were GCC, AAT and GAT. in GCC haplotype frequency distribution: the normal group vs group MACE 0.458 vs 0.539 P=0.031; AAT haplotype frequency distribution: normal group vs group MACE 0.465 vs 0.382, P=0.027, with statistical significance. Conclusion: 1. this study determined the effective clinical reference CLPM values range from 0.172 to 1.359 mu g/mL; the effective clinical reference value range of MAR is 15.21% ~ 59.54%. in the future, can be adjusted by clopidogrel in real-time monitoring of CLPM concentration and MAR value The dosage of.2. the number of diseased vessels, and the concentration of MAR and CLPM in patients with blood drug clopidogrel after MACE has a significant correlation among the number of diseased vessels, MAR was positively associated with MACE, was significantly related to the negative correlation of.3.MAR and CLPM concentration and treated with clopidogrel after bleeding blood concentration of CLPM and MACE. The MAR was negatively correlated with bleeding, blood concentration of CLPM and.4. CYP3A4 rs2242480 bleeding events were positively related to CT, rs35599367 GA and ABCB1 rs1128053 GA, rs2032582CA/T, rs1045642 GA and clopidogrel clinical curative effect were no significant correlation between.5. PXR rs3814057 AC, PXRrs3814058TC PXR and rs6785049 AG were significantly correlated with MACE, but no significant correlation with bleeding events. Homozygous MACE patients were significantly higher than those in wild type and mutant heterozygote, PXR SNPs and other clinical curative effect of clopidogrel has no significant correlation with.6. PXRrs678 5049-rs3814057-rs3814058 GCC haplotype and AAT haplotype were significantly correlated with MACE. GCC haplotype patients had an increased risk of MACE, and AAT haplotype patients had a lower risk of MACE.

【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R969

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