【摘要】：研究目的:研究瓣膜置換術(shù)后CYP2C9*2、CYP2C9*3、CYP4F2、GGCX、VKORC1-1173、VKORC1-1639基因多態(tài)性,用試驗(yàn)方法得出各基因型在華人漢族人群中的分布情況,得出各基因型及人口學(xué)、臨床等非遺傳因素對瓣膜置換術(shù)后華法林穩(wěn)定劑量的影響,建立華法林穩(wěn)定劑量的預(yù)測模型,以達(dá)到臨床個(gè)體化抗凝治療的目的。研究方法:收集天津市胸科醫(yī)院2012年10月15日至2014年12月20日,226例行瓣膜置換術(shù),且術(shù)后規(guī)律服用華法林三月及以上、INR達(dá)到目標(biāo)范圍內(nèi)患者,提取患者血液中DNA,設(shè)計(jì)目標(biāo)DNA引物,并應(yīng)用聚合酶鏈?zhǔn)椒磻?yīng)(polymerase chain reaction,PCR)技術(shù)擴(kuò)增上述位點(diǎn)基因,并應(yīng)用酶切技術(shù),以特定內(nèi)切酶切出相關(guān)基因,以電泳顯示最終結(jié)果,得出目標(biāo)DNA基因序列,回顧追蹤患者服藥劑量,臨床資料、人口學(xué)特征,并長期監(jiān)測其INR,結(jié)合有無出血、血栓形成,應(yīng)用統(tǒng)計(jì)學(xué)方法,計(jì)算出各遺傳及非遺傳因素對華法林穩(wěn)定劑量影響大小,得出瓣膜置換術(shù)后華法林穩(wěn)定劑量預(yù)測模型。研究結(jié)果:(1)選取患者中VKORC-1639GA基因型分布為:AA型、AG型、GG型分別分別占88.3%、11.2%、0.05%,等位基因頻率分別為:93.9%和6.1%;VKROC-1173CT基因型分布為:TT、TC、CC分別占84.6%、14.9%、0.05%,等位基因頻率分別為93.9%和6.1%;CYP2C9*3基因型分布為:*1/*1、*1/*3、*3/*3分別占分別占92%、8%、0%,等位基因頻率分別為96%和4%;CYP2C9*2基因型分布為:*1/*1、*1/*2、*2/*2分別占98.9%、1.1%,等位基因頻率分別為99.5%、0.5%;CYP4F2(rs2108622)基因型分布為:CC、CT、TT分別占56.4%、36.7%、6.9%,等位基因頻率分別為:74.7%、25.3%;GGCX(rs6738645)基因型分布為:TT、GT、GG分別占41.5%、50.0%、8.5%,等位基因頻率分別為:66.5%、33.5%;(2)得出華法林穩(wěn)定計(jì)量預(yù)測模型Y=2.131-1.816VKORC1-1173+0.369GG CX+1.529BSA-0.013Age(Y為華法林穩(wěn)定劑量,單位為mg,VKORC1-1173當(dāng)基因型為TT型時(shí),取1,非TT型取0,當(dāng)GGCX為GT型時(shí)取1,非GT型取0,BSA單位為m2,Age單位為歲)研究結(jié)論:華法林穩(wěn)定劑量與體表面積、年齡、VKORC1-1173、GGCX基因型相關(guān),與CYP2C9*2、CYP2C9*3、CYP4F2、VKORC1-1639無明顯線性關(guān)系。其中VKORC1-1173的TT基因型與年齡與華法林穩(wěn)定劑量呈負(fù)相關(guān),而GGCX的GT基因型與體表面積與華法林穩(wěn)定劑量呈正相關(guān)。且VKORC1對華法林劑量的影響比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.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R654.2

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