本文關(guān)鍵詞：PCI術(shù)后患者PXR、CYP3A4和ABCB1基因多態(tài)性與氯吡格雷臨床療效的關(guān)聯(lián)性分析　出處：《安徽醫(yī)科大學》2016年碩士論文　論文類型：學位論文

  更多相關(guān)文章： PCI PXR CYP3A4 ABCB1 基因多態(tài)性 氯吡格雷 臨床療效

【摘要】：目的考察PCI術(shù)后患者PXR、CYP3A4和ABCB1基因多態(tài)性與氯吡格雷臨床療效的關(guān)聯(lián)。方法納入自2014年6月到2015年9月在安徽省某三甲醫(yī)院行PCI術(shù)的住院患者,所有患者均接受標準的雙聯(lián)抗血小板治療方案(口服氯吡格雷負荷劑量300mg/d+維持劑量75mg/d,口服阿司匹林負荷劑量100mg/d+維持劑量1OOmg/d,術(shù)后至少服用12個月)。于氯吡格雷血藥濃度穩(wěn)態(tài)狀態(tài)下,晨起空腹靜脈采血5mL,分別測定氯吡格雷羧酸代謝物(CLPM)血藥谷濃度、血小板最大聚集率(MAR),并采用Sequenom MassArray系統(tǒng)進行PXR、CYP3A4和ABCB1基因分型。通過再入院記錄、門診或電話隨訪患者術(shù)后12個月內(nèi)終點事件發(fā)生情況。運用SPSS17.0統(tǒng)計軟件和Haploview 4.2遺傳分析軟件研究基因多態(tài)性與氯吡格雷臨床療效的關(guān)聯(lián)。結(jié)果1.共收集符合條件的患者384例,術(shù)后12個月內(nèi)預(yù)后良好的患者共202例定義為正常組,發(fā)生不良心血管事件(MACE)的患者共153例定義為MACE組,出血事件的患者共29例定義為出血組。CLPM血藥濃度：正常組 vsMACE組(0.573±0.355)μg/mL vs(0.346±0.142)1μg/mL,P0.05；正常組vs出血組(0.573±0.355)1μg/mLvs(1.669±0.280)μg/mL,P0.05;CLPM的臨床有效參考值范圍為0.172-1.3591μg/mL。MAR:正常組vsMACE組(34.79±10.76)%vs(59.90±7.15)%,P0.05；正常組vs出血組(34.79±10.76)%vs(20.10±7.50)%,P0.05；MAR的臨床有效參考值范圍為15.21%～59.54%。Pearson相關(guān)性分析顯示CLPM血藥濃度與MAR呈顯著的負相關(guān),相關(guān)系數(shù)為r=-0.850,P=0.000。Logistic回歸分析顯示冠脈病變血管數(shù)是MACE的危險因素。2.分析等位基因和基因型頻率與終點事件關(guān)聯(lián)：PXR rs3814057C:正常組vs MACE組0.460 vs 0.546,P=0.O243; PXR rs3814058 C:正常組vs MACE組0.460 vs 0.543,P=0.0293; PXR rs6785049 G:正常組vs MACE組0.532 vs 0.611,P=0.0356。顯性模型條件下不同基因型患者MACE發(fā)生率的比較：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,具有統(tǒng)計學意義。以上結(jié)果提示,PXR rs3814057、PXR rs3814058和PXR rs6785049位點基因多態(tài)性與MACE顯著相關(guān),但與出血事件發(fā)生無顯著相關(guān)性,且 CYP3A4、ABCB1及除上述3個位點之外的其他PXR SNPs等位基因和基因型頻率與終點事件均無顯著相關(guān)性。3.分析單體型頻率與終點事件關(guān)聯(lián)：PXR rs1523130、rs3814055、rs1523127、rs2276706四個位點連鎖不平衡,共形成2種單體型為CCAG和TTCA, PXRrs6785049、rs3814057、rs3814058三個位點連鎖不平衡,共形成3種單體型分別為GCC、AAT和GAT。其中單體型GCC頻率分布：正常組vs MACE組0.458 vs 0.539,P=0.031；單體型AAT頻率分布：正常組vs MACE組0.465 vs 0.382,P=0.027,具有統(tǒng)計學意義。結(jié)論1.本研究確定了CLPM的臨床有效參考值范圍為0.172～1.359μg/mL; MAR的臨床有效參考值范圍為15.21%～59.54%。今后,可通過實時監(jiān)測CLPM濃度和MAR值來調(diào)整氯吡格雷的給藥劑量。2.病變血管數(shù)、MAR及CLPM血藥濃度與患者服用氯吡格雷后MACE的發(fā)生顯著相關(guān),其中病變血管數(shù)、MAR與MACE呈正相關(guān),CLPM血藥濃度與MACE呈負相關(guān)。3.MAR及CLPM血藥濃度與患者服用氯吡格雷后出血事件的發(fā)生顯著相關(guān),其中MAR與出血事件呈負相關(guān),CLPM血藥濃度與出血事件呈正相關(guān)。4. CYP3A4 rs2242480 CT、rs35599367 GA和ABCB1 rs1128053 GA、rs2032582CA/T、rs1045642 GA與氯吡格雷臨床療效無顯著相關(guān)性。5. PXR rs3814057 AC、PXRrs3814058TC和PXR rs6785049 AG與MACE顯著相關(guān),但與出血事件無明顯關(guān)聯(lián),突變型純合子患者MACE發(fā)生率顯著高于野生型和突變型雜合子,PXR其他SNPs與氯吡格雷臨床療效無顯著相關(guān)性。6. PXRrs6785049-rs3814057-rs3814058 GCC單體型和AAT單體型與MACE顯著相關(guān),GCC單體型患者MACE發(fā)生風險增加,AAT單體型患者MACE發(fā)生風險降低。
[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.

【學位授予單位】：安徽醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R969

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