基因多态性对中国非瓣膜性心房颤动患者服用华法林剂量的影响  

Effect of gene polymorphism on warfarin dosage in Chinese Han patients with nonvalvular atrial fibrillation

作　　者：杨晨光[1] 任怡荣 陈浩[1] 戴大鹏[3] 汪芳[1] Yang Chenguang;Ren Yirong;Chen Hao;Dai Dapeng;Wang Fang(Department of Cardiology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China;Graduate School of Peking Union Medical College,Beijing 100730,China;The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Beijing Hospital,National Center of Gerontology,National Health Commission,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China)

机构地区：[1]北京医院心内科,国家老年医学中心,中国医学科学院老年医学研究院,100730 [2]北京协和医学院研究生院,100730 [3]北京医院,国家老年医学中心,国家卫生健康委北京老年医学研究所,国家卫生健康委北京老年医学重点实验室,中国医学科学院老年医学研究院,100730

出　　处：《中华全科医师杂志》2020年第12期1175-1180,共6页Chinese Journal of General Practitioners

基　　金：十三五国家科技重大新药创制专项课题(2017ZX09304026);首都卫生发展科研专项(重点)(首发2016-1-4051);国家自然科学基金(81570307)。

摘　　要：目的研究中国非瓣膜性心房颤动(简称房颤)患者人群CYP2C9及VKORC1多态性与华法林抗凝治疗稳态剂量个体差异性之间的相关性;并结合多项非遗传因素,建立华法林稳态剂量的预测模型。方法回顾性筛选2016年1月至2019年5月在北京医院、同仁医院、宣武医院、安贞医院、天坛医院心内科服用华法林抗凝治疗的汉族房颤患者,共计544例。检测其CYP2C9基因的第1、2、3和7号外显子以及VKORC1第1639号位点的基因型和等位基因频率,同时记录患者基本信息、华法林稳态剂量、合并用药情况。结果共得到4种CYP2C9基因型:CYP2C9*1*1(93.57%,509/544)、CYP2C9*1*2(0.18%,1/544)、CYP2C9*1*3(5.88%,32/544)和CYP2C9*1*60(0.37%,2/544)。VKORC1基因多态性检测到3种基因型,AA(82.72%,450/544),GA(15.99%,87/544)和GG(1.29%,7/544)。在达到抗凝指标(国际化标准比值2.0~3.0)后,CYP2C9*1*1与VKORC1 GA/GG的患者华法林稳态剂量最高,可达(3.70±1.34)mg/d,两种基因均为突变型(CYP2C9*1*2,*1*3,*1*60与VKORC1-GA,GG)的患者华法林稳态剂量最低,为(2.17±0.29)mg/d(F=22.09,P<0.01)。多元线性回归分析结果显示体表面积、是否联用胺碘酮、CYP2C9及VKORC1基因型华法林稳态剂量的独立影响因素(t值分别为4.44、-2.90、-6.96、2.14,P<0.05),建立了华法林稳态剂量预测模型。结论体重、身高、体表面积、性别、吸烟及联用胺碘酮对房颤患者的华法林稳态剂量能够产生影响,CYP2C9和VKORC1突变基因型与华法林稳态剂量明显相关;根据遗传因素和其他影响因素构建的预测模型能够有效预测非瓣膜性房颤患者华法林的稳态剂量。Objectives To investigate the relationships between CYP2C9 and VKORC1 polymorphism and the steady-state dose of warfarin in Chinese Han patients with nonvalvular atrial fibrillation.Methods A total 544 Chinese Han patients with atrial fibrillation who received warfarin anticoagulant therapy in Department of Cardiology of Beijing Hospital,Tongren Hospital,Xuanwu Hospital,Anzhen Hospital and Tiantan Hospital were enrolled from January 2016 to may 2019.The genotype and allele frequency in exon 1,2,3,7 of CYP2C9 gene and 1639 site of VKORC1 gene were analyzed;and the general information,warfarin steady-state dose and concomitant medication of patients were recorded.Results There were four genotypes CYP2C9:CYP2C9*1*1(93.57%,509/544),CYP2C9*1*2(0.18%,1/544),CYP2C9*1*3(5.88%,32/544)and CYP2C9*1*60(0.37%,2/544);while VKORC1 had three genotypes:AA(82.72%,450/544),GA(15.99%,87/544)and GG(1.29%,7/544).After reaching the anticoagulation index(INR 2.0-3.0),the steady-state dose of warfarin was the highest in patients with CYP2C9*1/*1 and VKORC1 GA/GG genotypes,reaching(3.70±1.34)mg/d.The lowest steady-state dose of warfarin was(2.17±0.29)mg/d in patients with both new mutations(F=22.09,P<0.001).Multiple linear regression analysis showed that body surface area,use of amiodarone,CYP2C9 and VKORC1 genotypes were the independent influencing factors of warfarin steady-state dose(t=4.44,-2.90,-6.96,2.14;P<0.05)and the steady-state dose prediction model of warfarin was established.Conclusion Body weight,height,body surface area,gender,smoking,and combination of amiodarone may significantly affect the steady-state dose of warfarin in patients.CYP2C9 and VKORC1 mutant genotypes were significantly related to the steady-state dose of warfarin.The prediction model based on genetic factors and other influencing factors may effectively predict the steady-state dose of warfarin in Han patients with atrial fibrillation.

关 键 词：心房颤动 多态性 单核苷酸 华法林 

分 类 号：R542.22[医药卫生—心血管疾病]