心脏瓣膜置换术后华法林个体化治疗预测模型研究

发布时间：2018-11-09 14:54

【摘要】：研究目的:研究瓣膜置换术后CYP2C9*2、CYP2C9*3、CYP4F2、GGCX、VKORC1-1173、VKORC1-1639基因多态性,用试验方法得出各基因型在华人汉族人群中的分布情况,得出各基因型及人口学、临床等非遗传因素对瓣膜置换术后华法林稳定剂量的影响,建立华法林稳定剂量的预测模型,以达到临床个体化抗凝治疗的目的。研究方法:收集天津市胸科医院2012年10月15日至2014年12月20日,226例行瓣膜置换术,且术后规律服用华法林三月及以上、INR达到目标范围内患者,提取患者血液中DNA,设计目标DNA引物,并应用聚合酶链式反应(polymerase chain reaction,PCR)技术扩增上述位点基因,并应用酶切技术,以特定内切酶切出相关基因,以电泳显示最终结果,得出目标DNA基因序列,回顾追踪患者服药剂量,临床资料、人口学特征,并长期监测其INR,结合有无出血、血栓形成,应用统计学方法,计算出各遗传及非遗传因素对华法林稳定剂量影响大小,得出瓣膜置换术后华法林稳定剂量预测模型。研究结果:(1)选取患者中VKORC-1639GA基因型分布为:AA型、AG型、GG型分别分别占88.3%、11.2%、0.05%,等位基因频率分别为:93.9%和6.1%;VKROC-1173CT基因型分布为:TT、TC、CC分别占84.6%、14.9%、0.05%,等位基因频率分别为93.9%和6.1%;CYP2C9*3基因型分布为:*1/*1、*1/*3、*3/*3分别占分别占92%、8%、0%,等位基因频率分别为96%和4%;CYP2C9*2基因型分布为:*1/*1、*1/*2、*2/*2分别占98.9%、1.1%,等位基因频率分别为99.5%、0.5%;CYP4F2(rs2108622)基因型分布为:CC、CT、TT分别占56.4%、36.7%、6.9%,等位基因频率分别为:74.7%、25.3%;GGCX(rs6738645)基因型分布为:TT、GT、GG分别占41.5%、50.0%、8.5%,等位基因频率分别为:66.5%、33.5%;(2)得出华法林稳定计量预测模型Y=2.131-1.816VKORC1-1173+0.369GG CX+1.529BSA-0.013Age(Y为华法林稳定剂量,单位为mg,VKORC1-1173当基因型为TT型时,取1,非TT型取0,当GGCX为GT型时取1,非GT型取0,BSA单位为m2,Age单位为岁)研究结论:华法林稳定剂量与体表面积、年龄、VKORC1-1173、GGCX基因型相关,与CYP2C9*2、CYP2C9*3、CYP4F2、VKORC1-1639无明显线性关系。其中VKORC1-1173的TT基因型与年龄与华法林稳定剂量呈负相关,而GGCX的GT基因型与体表面积与华法林稳定剂量呈正相关。且VKORC1对华法林剂量的影响比GGCX大。
[Abstract]:Objective: to study the polymorphism of CYP2C9*2,CYP2C9*3,CYP4F2,GGCX,VKORC1-1173,VKORC1-1639 gene after valvular replacement, and to obtain the distribution of the genotypes in the Chinese Han population, and to obtain the genotypes and demographics. The effect of clinical and other non-genetic factors on the stable dose of warfarin after valvular replacement was studied. A predictive model of warfarin stable dose was established to achieve the purpose of individualized anticoagulant therapy. Methods: from October 15, 2012 to December 20, 2014, 226 patients with valvular replacement were treated regularly with warfarin for three months or more. INR was used to reach the target range. DNA, was extracted from patients' blood. The target DNA primers were designed and amplified by polymerase chain reaction (polymerase chain reaction,PCR) technique. The related genes were digested by specific endonuclease and the target DNA gene sequence was obtained by electrophoretic analysis. The dosages, clinical data, demographic characteristics of the patients were retrospectively tracked, and their INR, combined with bleeding and thrombosis were monitored for a long time. The effects of genetic and non-genetic factors on the stable dose of warfarin were calculated by statistical method. The stable dose prediction model of warfarin after valvular replacement was obtained. The results were as follows: (1) the distribution of VKORC-1639GA genotypes were as follows: AA type, AG type and GG type accounted for 88.311.2and 0.05, respectively. The frequency of alleles were 93.9% and 6.1%, respectively. The distribution of VKROC-1173CT genotypes was as follows: TT,TC,CC accounted for 84.6% and 14.9%, and allele frequencies were 93.9% and 6.1%, respectively. The distribution of CYP2C9*3 genotypes was as follows: * 1 / 1 / 1 / 1 / 3 / 3 / 3 / 9 / 2, respectively, and the allele frequencies were 96% and 4%, respectively. The distribution of CYP2C9*2 genotypes was as follows: * 1 / 1 / 1 / 1 / 1 / 2 / 2 / 2 of 98.9 / 1 / 2, respectively, and the allele frequencies were 99.5% and 0.5%, respectively. The distribution of CYP4F2 (rs2108622) genotypes was as follows: CC,CT,TT accounted for 56.4% and 36.7%, and the allele frequencies were 74.7% and 25.3%, respectively. The distribution of GGCX (rs6738645) genotypes was as follows: TT,GT,GG accounted for 41.5% and 50.0%, and the allelic frequencies were 66.5% and 33.5%, respectively. (2) the warfarin stability prediction model Y=2.131-1.816VKORC1-1173 0.369GG CX 1.529BSA-0.013Age (Y is warfarin stable dose) is obtained. The unit of warfarin stable dose is mg,VKORC1-1173. When the genotype is TT, 1 is selected, and 0 is non-TT. Conclusion: warfarin stabilizer is correlated with body surface area, age, VKORC1-1173,GGCX genotype and CYP2C9*2,CYP2C9*3,CYP4F2,. VKORC1-1639 has no obvious linear relationship. There was a negative correlation between TT genotype and age of VKORC1-1173 and stable dose of warfarin, but a positive correlation between genotype of GT and area of body surface of GGCX and stable dose of warfarin. The effect of VKORC1 on warfarin dose was greater than that of GGCX.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R654.2

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