PXR和VKORC1基因多态性对华法林维持剂量的影响
摘要
研究目的：华法林在临床上的抗凝治疗剂量受到许多基因多态性的影响,核受体PXR作为转录调控因子,调控华法林在体内代谢、转运等过程中相关基因的表达。维生素K环氧化物还原酶(VKOR)是华法林的作用靶点,研究也证实了其基因多态性是影响华法林剂量的种族差异和个体差异的主要因素。本课题的研究目的旨在探讨孕烷X受体(PXR)和维生素K环氧化物还原酶复合物1基因(VKORC1)-1639G＞A多态性对机械瓣膜置换术后患者华法林维持剂量的影响。
研究方法：收集215例心脏机械瓣膜置换术患者的基本临床特征和华法林维持剂量,并采集外周静脉血5ml用于DNA提取,采用PCR-RFLP方法进行VKORC1-1639G＞A基因分型,Allelic Special-Touch Down PCR方法进行PXR6碱基缺失突变(rs3842689)分型。比较VKORC1-1639G＞A, PXR rs3842689各基因型之间的华法林维持剂量,以分析这二种基因多态性对华法林维持剂量的影响。比较分析性别、年龄和体重对华法林维持剂量的影响。
结果：在215例患者中,VKORC1-1639G＞A位点基因型分别为：AA型186个(86.5%),AG型28个(13.0%),GG型1个(0.5%)。携带VKORC1-1639 G等位基因的患者(AG和GG型)华法林日平均维持剂量显著高于AA型,AA型(2.8±1.0mg), AG/GG型(3.8±1.0mg),(P＜0.001)。PXR 6碱基缺失WW、WM、MM基因型频率分别为54.4%(117/215)、37.2%(80/215)和8.4%(18/215)。各基因型组之间的华法林日平均维持剂量分别是：WW (2.9±1.1mg)、WM (3.0±1.0mg)、MM(3.1±0.8mg),三组间均没差别(P=0.764)。均衡VKORC1-1639G＞A变异后,性别分层比较,仍未发现PXR6碱基缺失对华法林剂量有影响。男性患者的华法林日平均维持剂量为3.2±1.1mg/day,显著高于女性患者(2.8±1.0mg/day), (P=0.018)。单因素分析还发现体重与换瓣数也与华法林维持剂量相关,P值分别为0.037,0.024。未发现年龄与华法林维持剂量相关。多元线性回归分析发现VKORC1-1639G＞A和性别一共可以解释华法林个体差异性的12.2%。
结论：VKORC1-1639G＞A基因多态性对术后抗凝治疗患者华法林的维持剂量有显著影响,而PXR6碱基缺失突变(rs3842689)对华法林的维持剂量没有影响。男性患者华法林维持剂量显著高于女性,体重和置换瓣膜数与华法林治疗剂量正性相关,而年龄对于华法林的维持剂量则没有显著影响。
Objective:Warfarin dose requirement was influenced by many gene polymorphisms. Nuclear receptor PXR is a transcriptional control factor and control the expression of genes related to metabolism and transport process of warfarin. Recent genome-wide association studies confirmed VKORC1 as the principal genetic determinants of warfarin dose. The aims of our study were to investigate the polymorphisms of pregnane X receptor (PXR) and Vitamin K epoxide reductase complex subunit 1 (VKORC1-1639G>A) in patients with heart valve replaced as well as the possible relationship between the individual warfarin maintain dosage requirements and these genetic polymorphisms in Chinese.
Methods:Basic clinical feature and blood samples were collected from 215 Chinese patients who received mechanicalness cardiac valve replacement operated in Xiangya Hospital with stable warfarin dose requirement and an international normalized ratio (INR) of the prothrombin time within the target range of 1.5-3.0. The polymorphism of VKORC1-1639G>A in 215 patients was detected by using PCR-RFLP. PXR 6bp deletions (rs3842689) genotypes were determined by using Allelic Special-Touch down PCR method. The genotype and allelic frequencies were calculated and the individual warfarin maintenance dosage requirements were analyzed. The contributions of gender, age and body weight to warfarin dose requirement were also investigated.
Results:AA genotype was found in 186 patients (86.5%), AG genotype in 28 patients (13.0%) and GG genotype in 1 patient (0.5%). The mean warfarin dosage was significantly higher in patients with AG/GG genotype than that in patients with AA genotype, AA (2.8±1.0mg), AG/GG (3.8±1.0mg), (P＜0.001). The frequencies of the PXR 6bp deletion WW, WM, MM genotypes were 54.4%(117/215),37.2%(80 /215) and 8.4%(18/215), respectively. The mean warfarin dosages were:WW (2.9±1.1mg), WM (3.0±1.0mg), and MM (3.1±0.8mg). It showed no significant difference in mean warfarin dosage among the genotypes of PXR 6bp deletions (P=0.764). After adjusted VKORC1-1639G>A and gender, there were also no significant difference in warfarin dosage among the genotypes of PXR 6bp deletions. The warfarin dose of men was significantly higher than women, their dose were 3.2±1.1 mg/day,2.8±1.0 mg/day respectively,P=0.018. Body weight and the number of replaced valves except for age were found to be potentially associated with warfarin dose requirements. In the multiple linear regression model, the combination of gender and VKORC1-1639G>A could explain 12.2% of the variance in warfarin dose requirements.
Conclusions:Polymorphism of VKORC1-1639G>A is dominant factor causing difference of individual warfarin maintain dosage requirements in Han Chinese, while PXR 6bp deletion (rs3842689) had no significant influence on patients'warfarin dosage requirements. The warfarin dose of men was significantly higher than women. The number of replaced valves and body weight can positively influence patients'warfarin dose requirement. Age had no significant influence on patients'warfarin dose requirement.
研究方法：收集215例心脏机械瓣膜置换术患者的基本临床特征和华法林维持剂量,并采集外周静脉血5ml用于DNA提取,采用PCR-RFLP方法进行VKORC1-1639G＞A基因分型,Allelic Special-Touch Down PCR方法进行PXR6碱基缺失突变(rs3842689)分型。比较VKORC1-1639G＞A, PXR rs3842689各基因型之间的华法林维持剂量,以分析这二种基因多态性对华法林维持剂量的影响。比较分析性别、年龄和体重对华法林维持剂量的影响。
结果：在215例患者中,VKORC1-1639G＞A位点基因型分别为：AA型186个(86.5%),AG型28个(13.0%),GG型1个(0.5%)。携带VKORC1-1639 G等位基因的患者(AG和GG型)华法林日平均维持剂量显著高于AA型,AA型(2.8±1.0mg), AG/GG型(3.8±1.0mg),(P＜0.001)。PXR 6碱基缺失WW、WM、MM基因型频率分别为54.4%(117/215)、37.2%(80/215)和8.4%(18/215)。各基因型组之间的华法林日平均维持剂量分别是：WW (2.9±1.1mg)、WM (3.0±1.0mg)、MM(3.1±0.8mg),三组间均没差别(P=0.764)。均衡VKORC1-1639G＞A变异后,性别分层比较,仍未发现PXR6碱基缺失对华法林剂量有影响。男性患者的华法林日平均维持剂量为3.2±1.1mg/day,显著高于女性患者(2.8±1.0mg/day), (P=0.018)。单因素分析还发现体重与换瓣数也与华法林维持剂量相关,P值分别为0.037,0.024。未发现年龄与华法林维持剂量相关。多元线性回归分析发现VKORC1-1639G＞A和性别一共可以解释华法林个体差异性的12.2%。
结论：VKORC1-1639G＞A基因多态性对术后抗凝治疗患者华法林的维持剂量有显著影响,而PXR6碱基缺失突变(rs3842689)对华法林的维持剂量没有影响。男性患者华法林维持剂量显著高于女性,体重和置换瓣膜数与华法林治疗剂量正性相关,而年龄对于华法林的维持剂量则没有显著影响。
Objective:Warfarin dose requirement was influenced by many gene polymorphisms. Nuclear receptor PXR is a transcriptional control factor and control the expression of genes related to metabolism and transport process of warfarin. Recent genome-wide association studies confirmed VKORC1 as the principal genetic determinants of warfarin dose. The aims of our study were to investigate the polymorphisms of pregnane X receptor (PXR) and Vitamin K epoxide reductase complex subunit 1 (VKORC1-1639G>A) in patients with heart valve replaced as well as the possible relationship between the individual warfarin maintain dosage requirements and these genetic polymorphisms in Chinese.
Methods:Basic clinical feature and blood samples were collected from 215 Chinese patients who received mechanicalness cardiac valve replacement operated in Xiangya Hospital with stable warfarin dose requirement and an international normalized ratio (INR) of the prothrombin time within the target range of 1.5-3.0. The polymorphism of VKORC1-1639G>A in 215 patients was detected by using PCR-RFLP. PXR 6bp deletions (rs3842689) genotypes were determined by using Allelic Special-Touch down PCR method. The genotype and allelic frequencies were calculated and the individual warfarin maintenance dosage requirements were analyzed. The contributions of gender, age and body weight to warfarin dose requirement were also investigated.
Results:AA genotype was found in 186 patients (86.5%), AG genotype in 28 patients (13.0%) and GG genotype in 1 patient (0.5%). The mean warfarin dosage was significantly higher in patients with AG/GG genotype than that in patients with AA genotype, AA (2.8±1.0mg), AG/GG (3.8±1.0mg), (P＜0.001). The frequencies of the PXR 6bp deletion WW, WM, MM genotypes were 54.4%(117/215),37.2%(80 /215) and 8.4%(18/215), respectively. The mean warfarin dosages were:WW (2.9±1.1mg), WM (3.0±1.0mg), and MM (3.1±0.8mg). It showed no significant difference in mean warfarin dosage among the genotypes of PXR 6bp deletions (P=0.764). After adjusted VKORC1-1639G>A and gender, there were also no significant difference in warfarin dosage among the genotypes of PXR 6bp deletions. The warfarin dose of men was significantly higher than women, their dose were 3.2±1.1 mg/day,2.8±1.0 mg/day respectively,P=0.018. Body weight and the number of replaced valves except for age were found to be potentially associated with warfarin dose requirements. In the multiple linear regression model, the combination of gender and VKORC1-1639G>A could explain 12.2% of the variance in warfarin dose requirements.
Conclusions:Polymorphism of VKORC1-1639G>A is dominant factor causing difference of individual warfarin maintain dosage requirements in Han Chinese, while PXR 6bp deletion (rs3842689) had no significant influence on patients'warfarin dosage requirements. The warfarin dose of men was significantly higher than women. The number of replaced valves and body weight can positively influence patients'warfarin dose requirement. Age had no significant influence on patients'warfarin dose requirement.
引文
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