本文關(guān)鍵詞： 基因 多態(tài)性 中國 漢族 機(jī)械 瓣膜 置換 術(shù)后 患者 華法 林穩(wěn)態(tài) 穩(wěn)態(tài) 劑量 影響　出處：《中南大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：目的：華法林是臨床上最廣泛使用的口服抗凝藥,其治療窗窄,劑量個(gè)體間差異大,容易引發(fā)出血或栓塞。CYP2C9和VKORC1基因多態(tài)性可顯著影響華法林劑量。其他參與維生素K攝入和循環(huán),及華法林轉(zhuǎn)運(yùn)的基因變異也可能會(huì)影響華法林療效,具有調(diào)控基因作用的microRNA也可能影響華法林劑量。本課題旨在研究中國漢族機(jī)械瓣膜置換術(shù)患者中,基因單核苷酸多態(tài)性(SNP)對(duì)華法林穩(wěn)態(tài)劑量的影響。 方法：募集231例達(dá)到華法林穩(wěn)態(tài)劑量的中國漢族機(jī)械瓣膜置換術(shù)患者。利用SNaPshot、直接測(cè)序法和焦磷酸測(cè)序法檢測(cè)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。非參數(shù)檢驗(yàn)比較不同基因型患者間的華法林平均穩(wěn)定劑量差異。一元線性回歸和多元線性逐步回歸分析各基因多態(tài)性及其他非遺傳因素對(duì)華法林穩(wěn)定劑量的影響。 結(jié)果：VKORC1-1639GAAA、GA、GG基因型的分布頻率分別為79.7%、18.6%、1.7%；CYP2C9*3*1/*1、*1/*3的分布頻率分別為93.1%、6.9%:CYP4F2rs2108622GG、GA、AA分布頻率分別為62.8%、33.8%、3.4%;GGCX rs699664CC、CT、TT分布頻率分別為44.2%、46.8%、9.1%;GGCX rs12714145CC、CT、TT分布頻率分別40.1%、45.2%、14.7%；EPHX1rs4653436GG、GA、AA分布頻率分別64.5%、31.6%、3.9%；EPHX1rsl877724CC、CT、TT分布頻率分別43.3%、48.1%、8.6%；PROC rs5936TT.GT.GG分布頻率分別24.7%、54.1%、21.2%;F2rs5896TT、CT、CC分布頻率分別29.0%、52.4%、18.6%;APOE rs7412CC、CT分布頻率分別82.7%、17.3%；APOE rs429358TT、CT、CC分布頻率分別77.5%、21.2%、1.3%；miRNA133a-2-191GA GG、GA、AA基因型頻率分別為95.6%、2.2%、2.2%;miRNA133b-25ins/del A AA、A/-的分布頻率分別為92.2%、7.8%；由于miRNA133a-2-191GA不符合Hardy-Weinberg平衡,不予進(jìn)行后續(xù)分析。非秩和檢驗(yàn)結(jié)果顯示VKORC1-1639GA、 CYP2C9*3、CYP4F2rs2108622、GGCX (rs699664、rsl2714145)各基因型間劑量有顯著差異。一元線性回歸顯示年齡、BSA、 VKORC1-1639GA、CYP2C9*3、CYP4F2rs2108622、GGCX (rs699664、rs12714145)顯著影響華法林穩(wěn)態(tài)劑量(P0.05)。逐步多元線性回歸顯示VKORC1-1639G＞A、CYP2C9*3、CYP4F2rs2108622、年齡和BSA可以分別解釋25.1%、11.8%、2%、4%和2.1%的華法林穩(wěn)態(tài)劑量個(gè)體差異。EPHX1(rs4653436、rs1877724)、 GGCX (rs699664、rs12714145)、PROC rs5936、APOE (rs7412、 rs429358)、F2rs5896、miRNA133a-2-191GA、miRNA133b-25ins/delA對(duì)華法林穩(wěn)態(tài)劑量沒有顯著影響。 結(jié)論：在中國漢族人工心臟機(jī)械瓣膜置換術(shù)患者中,VKORC1-1639GA,CYP2C9*3, CYP4F2(rs2108622)基因多態(tài)性是影響華法林個(gè)體劑量差異的主要遺傳因素。VKORC1-1639GA、 CYP2C9*3、CYP4F2rs2108622、年齡和BSA分別可以解釋25.1%、11.8%、2%、4%、2.1%個(gè)體間華法林劑量差異。
[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

【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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本文編號(hào)：1544795