基因多态性对中国汉族机械瓣膜置换术后患者华法林稳态剂量的影响

发布时间：2018-02-27 23:32

本文关键词： 基因多态性中国汉族机械瓣膜置换术后患者华法林稳态稳态剂量影响　出处：《中南大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的：华法林是临床上最广泛使用的口服抗凝药,其治疗窗窄,剂量个体间差异大,容易引发出血或栓塞。CYP2C9和VKORC1基因多态性可显著影响华法林剂量。其他参与维生素K摄入和循环,及华法林转运的基因变异也可能会影响华法林疗效,具有调控基因作用的microRNA也可能影响华法林剂量。本课题旨在研究中国汉族机械瓣膜置换术患者中,基因单核苷酸多态性(SNP)对华法林稳态剂量的影响。方法：募集231例达到华法林稳态剂量的中国汉族机械瓣膜置换术患者。利用SNaPshot、直接测序法和焦磷酸测序法检测VKORC1-1639GA、CYP2C9*3、CYP4F2rs2108622.EPHX1(rs4653436、 rs1877724)、GGCX(rs699664、rs12714145)、PROC rs5936、APOE (rs7412、rs429358)、F2rs5896、miRNA133a-2-191GA.miRNA133b-25ins/del A基因型。非参数检验比较不同基因型患者间的华法林平均稳定剂量差异。一元线性回归和多元线性逐步回归分析各基因多态性及其他非遗传因素对华法林稳定剂量的影响。结果：VKORC1-1639GAAA、GA、GG基因型的分布频率分别为79.7%、18.6%、1.7%；CYP2C9*3*1/*1、*1/*3的分布频率分别为93.1%、6.9%:CYP4F2rs2108622GG、GA、AA分布频率分别为62.8%、33.8%、3.4%;GGCX rs699664CC、CT、TT分布频率分别为44.2%、46.8%、9.1%;GGCX rs12714145CC、CT、TT分布频率分别40.1%、45.2%、14.7%；EPHX1rs4653436GG、GA、AA分布频率分别64.5%、31.6%、3.9%；EPHX1rsl877724CC、CT、TT分布频率分别43.3%、48.1%、8.6%；PROC rs5936TT.GT.GG分布频率分别24.7%、54.1%、21.2%;F2rs5896TT、CT、CC分布频率分别29.0%、52.4%、18.6%;APOE rs7412CC、CT分布频率分别82.7%、17.3%；APOE rs429358TT、CT、CC分布频率分别77.5%、21.2%、1.3%；miRNA133a-2-191GA GG、GA、AA基因型频率分别为95.6%、2.2%、2.2%;miRNA133b-25ins/del A AA、A/-的分布频率分别为92.2%、7.8%；由于miRNA133a-2-191GA不符合Hardy-Weinberg平衡,不予进行后续分析。非秩和检验结果显示VKORC1-1639GA、 CYP2C9*3、CYP4F2rs2108622、GGCX (rs699664、rsl2714145)各基因型间剂量有显著差异。一元线性回归显示年龄、BSA、 VKORC1-1639GA、CYP2C9*3、CYP4F2rs2108622、GGCX (rs699664、rs12714145)显著影响华法林稳态剂量(P0.05)。逐步多元线性回归显示VKORC1-1639G＞A、CYP2C9*3、CYP4F2rs2108622、年龄和BSA可以分别解释25.1%、11.8%、2%、4%和2.1%的华法林稳态剂量个体差异。EPHX1(rs4653436、rs1877724)、 GGCX (rs699664、rs12714145)、PROC rs5936、APOE (rs7412、 rs429358)、F2rs5896、miRNA133a-2-191GA、miRNA133b-25ins/delA对华法林稳态剂量没有显著影响。结论：在中国汉族人工心脏机械瓣膜置换术患者中,VKORC1-1639GA,CYP2C9*3, CYP4F2(rs2108622)基因多态性是影响华法林个体剂量差异的主要遗传因素。VKORC1-1639GA、 CYP2C9*3、CYP4F2rs2108622、年龄和BSA分别可以解释25.1%、11.8%、2%、4%、2.1%个体间华法林剂量差异。
[Abstract]:Objective: Hua Falin is the most widely used oral anticoagulant in clinical, its narrow therapeutic window, individual dose, easily lead to bleeding or thrombosis and.CYP2C9 polymorphism of VKORC1 gene can significantly affect Hua Falin dose. Others involved in vitamin K intake and circulation, gene mutation and Hua Falin transfer may also influence the Hua Falin effect. With the role of the microRNA gene may affect the dose of Hua Falin. This paper aims at the study of Han China mechanical heart valve replacement in patients with single nucleotide polymorphism (SNP) effect on the Hua Falin steady dose.
Methods: 231 cases of Han China raise mechanical valve replacement patients reached steady state. By using the SNaPshot dose of warfarin, VKORC1-1639GA detection, direct sequencing and pyrosequencing method CYP2C9*3, CYP4F2rs2108622.EPHX1 (rs4653436, rs1877724), GGCX (rs699664, rs12714145), PROC rs5936, APOE (rs7412, rs429358), F2rs5896, miRNA133a-2-191GA.miRNA133b-25ins/del A genotype the non parametric test. Different genotypes were compared between patients with the average amount of warfarin stabilizer difference. A linear regression and multiple linear regression analysis of the influence of gene polymorphism and other non genetic factors on warfarin stable dose.
Results: VKORC1-1639GAAA, GA, GG genotypes were 79.7%, 18.6%, 1.7%; CYP2C9*3*1/*1, the frequency distribution of *1/*3 were 93.1%, 6.9%, CYP4F2rs2108622GG, GA, AA distribution frequencies were 62.8%, 33.8%, 3.4%; GGCX, rs699664CC, CT, TT frequency distribution rates were 44.2%, 46.8%, 9.1%; GGCX rs12714145CC, CT TT, the frequency distribution of respectively 40.1%, 45.2%, 14.7%; EPHX1rs4653436GG, GA, AA distribution frequencies were 64.5%, 31.6%, 3.9%; EPHX1rsl877724CC, CT, TT distribution frequencies were 43.3%, 48.1%, 8.6%; PROC rs5936TT.GT.GG distribution frequencies were 24.7%, 54.1%, 21.2%; F2rs5896TT, CT, CC distribution frequencies were 29%. 52.4%, 18.6%; APOE rs7412CC, CT distribution frequencies were 82.7%, 17.3%; APOE, rs429358TT, CT, CC distribution frequency respectively 77.5%, 21.2%, 1.3%; miRNA133a-2-191GA, GG, GA, AA genotype frequencies were 95.6%, 2.2%, 2.2%; miRNA133b-25ins/del A AA, A/-'s Distribution frequencies were 92.2%, 7.8%; because the miRNA133a-2-191GA does not meet the Hardy-Weinberg balance, not for subsequent analysis. Non rank test results showed that VKORC1-1639GA, CYP2C9*3, CYP4F2rs2108622, GGCX (rs699664, rsl2714145) among genotypes dose had significant difference. A linear regression showed that age, BSA, VKORC1-1639GA, CYP2C9*3, CYP4F2rs2108622, GGCX (rs699664, rs12714145) significantly affect the steady-state warfarin dose (P0.05). VKORC1-1639G, stepwise multiple linear regression of A, CYP2C9*3, CYP4F2rs2108622, and BSA may be explained by age 25.1%, respectively, 11.8%, 2%, and 4% individual differences in steady-state warfarin dose 2.1%.EPHX1 (rs4653436, rs1877724), GGCX (rs699664, rs12714145), PROC rs5936 APOE, (rs7412, rs429358), F2rs5896, miRNA133a-2-191GA, miRNA133b-25ins/delA had no significant effect on the steady-state warfarin dose.
Conclusion: in Chinese Han artificial mechanical heart valve replacement patients, VKORC1-1639GA, CYP2C9*3, CYP4F2 (rs2108622) gene polymorphism is the main genetic effects of.VKORC1-1639GA and warfarin individual dose difference factors CYP2C9*3, CYP4F2rs2108622, age and BSA respectively accounted for 25.1%, 11.8%, 2%, 4%, 2.1%. The difference between individual warfarin dose

【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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