少见细胞色素P4502C9等位基因对中国汉族心房颤动患者华法林稳态剂量的影响及预测模型的构建

Impacts of Rare CYP2C9 Alleles on Stable Warfarin Dosage in Chinese Han Patients With Atrial Fibrillation and the Establishment of Prediction Model Based on Rare CYP2C9 Alleles

目的:探究除细胞色素P450 2C9(CYP2C9)*2和CYP2C9*3以外的少见CYP2C9等位基因对中国汉族心房颤动患者华法林稳态剂量的影响,并构建新的预测模型。方法:选取2011年1月至2017年3月在我院接受华法林抗凝治疗的心房颤动患者681例,随机以2:1的比例分为建模组(n=454)和验证组(n=227)。采用PCR直接测序分析CYP2C9和维生素K环氧化物还原酶复合体1 (VKORC1)基因型,通过单因素相关分析筛选与华法林稳态剂量相关的变量,采用多元线性回归分析建立华法林稳态剂量预测模型。结果:发现了三种少见CYP2C9等位基因(CYP2C9*13、*16、*60),均为杂合子。综合这三种少见基因型,建立变量CYP2C9(13/16/60),其华法林稳态剂量显著低于CYP2C9*1/*1(P<0.001)及CYP2C9*1/*3(P<0.05)。构建中国汉族人群特异的包含有其他少见CYP2C9基因突变变量的华法林稳态剂量预测方程,华法林日剂量=exp[0.524+0.344×体表面积-0.082×胺碘酮-0.393×CYP2C9*3-0.740×CYP2C9(13/16/60)+0.276×VKORC1-1639GA+0.593×VKORC1-1639GG] R^2=44.3%。其中CYP2C9(13/16/60)占总基因型频率的0.7%,但可以解释6.3%的华法林剂量个体差异。将研究模型应用于验证组,相关系数达0.567。结论:CYP2C9*13、*16、*60等位基因与更低的华法林稳态剂量相关,新构建的纳入有上述少见CYP2C9等位基因变量的预测方程可以更好地预测中国汉族人群华法林稳态剂量。

Objectives:To investigate the impact of rare cytochrome P4502C9(CYP2C9)alleles except CYP2C9*2 and CYP2C9*3 on stable warfarin dosage in Chinese Han patients with atrial fibrillation and establish a new prediction model based on rare CYP2C9 alleles.Methods:A total of 681 atrial fibrillation patients who received anticoagulant therapy with warfarin in our hospital from January 2011 to March 2017 were randomly divided into the modeling group(n=454)and the validation group(n=227)at a ratio of 2:1.The genotypes of CYP2C9 and vitamin K epoxide reductase complex subunit 1(VKORC1)were directly sequenced by polymerase chain reaction.The variables related to the stable warfarin dosage were selected by univariate analyses,and the warfarin-dosing algorithm was derived by multivariate regression analysis.Results:Three rare CYP2C9 alleles(CYP2C9*13,*16,*60)were found,all of which were heterozygous.A new variable CYP2C9(13/16/60)was established by combining the three rare alleles,whose stable warfarin dosage was significantly lower than that of CYP2C9*1/*1(P<0.001)and CYP2C9*1/*3(P<0.05).We constructed a warfarin-dosing algorithm specific to Han Chinese containing a variable related to these rare CYP2C9 alleles.Stable daily warfarin dose=exp[0.524+0.344×BSA-0.082×Amiodarone-0.393×CYP2C9*3-0.740×CYP2C9(13/16/60)+0.276×VKORC1-1639GA+0.593×VKORC1-1639GG]R^2=44.3%.CYP2C9(13/16/60)accounts for 0.7%of the total genotype frequency,but presence or absence of CYP2C9(13/16/60)could explain 6.3%interindividual variability of the warfarin dose requirements.Applying the model to the verification group,the correlation coefficient reached 0.567.Conclusions:CYP2C9*13,*16,*60 is associated with lower stable warfarin dosage.The newly developed prediction model including such rare CYP2C9 allele can better predict the stable warfarin dosage in Chinese Han population with atrial fibrillation.