受者CYP3A5基因多态性对心脏移植术后血他克莫司浓度的影响  

Effect of CYP3A5 polymorphisms on tacrolimus concentration and acute organ rejection incidence after heart transplantation in recipients

作　　者：刘冰洋[1] 柳青[1] 郑哲[1] 黄洁[1] 廖中凯[1] 宋云虎[1] 王巍[1] 胡盛寿[1] Liu Bingyang Liu Qing Zheng Zhe Huang Jie Liao Zhongkai Song Yunhu Wang Wei Hu Shengshou(Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China)

机构地区：[1]北京协和医学院中国医学科学院国家心血管病中心阜外医院,100037

出　　处：《中华器官移植杂志》2017年第5期262-266,共5页Chinese Journal of Organ Transplantation

摘　　要：目的 研究细胞色素P450 3A酶系（CYP3A）中CYP3A5基因多态性对心脏移植受者他克莫司剂量、血药浓度以及临床结果的影响.方法 113例受者术后使用他克莫司的心脏移植受者,其中41例术后1年内始终使用他克莫司,72例术后1年内将环孢素A更换为他克莫司.利用MassARRAY分子量阵列技术平台检测受者的CYP3A5基因型,比较各基因型受者不同时间血他克莫司浓度谷值与剂量比值（C0/D）,进行心内膜心肌活检诊断急性排斥反应,观察急性排斥反应导致的死亡率及全因死亡率.结果 113例受者中,野生纯合子（＊1/＊1型）占4.4％,突变杂合子（＊1/＊3型）占30.1％,突变纯合子（＊3/＊3型）占65.5％.3组基因型受者术后1个月的C0/D值分别为47.34±11.40、116.11±42.40和293.70±171.20,三者比较,差异均有统计学意义（P =0.000）.41例术后1年内始终应用他克莫司的受者中,＊1/＊3型有10例,＊3/＊3型有31例,二者术后1个月的C0/D值分别为134.23±57.30和323.00±128.67（P=0.000）,3个月分别为98.32±39.43和292.07±141.08（P=0.003）,6个月分别为90.00±21.31和341.68±165.02（P=0.002）,12个月分别为96.02±29.33和339.23±162.30（P-0.018）;术后1、3、6个月心内膜心肌活检分值分别为1.50±0.58和1.43±0.73（P=0.867）,2.00±1.73和1.55±1.00（P=0.512）,2.33±1.53和1.36±0.84（P=0.132）;因急性排斥反应所致的死亡率分别为10％和0（P=0.244）,全因死亡率分别为20％和9.7％（P=0.580）.结论 CYP3A5基因突变在我国心脏移植受者中高达80.5％,术前检测受者CYP3A5基因型有助于指导他克莫司个体化用药.Objective To evaluate the effect of CYP3A5 genetic polymorphisms on tacrolimus （Tac） concentration/dosing and other clinical outcomes in a pilot cohort of 113 Chinese HTx recipients.Methods Association between CYP3A5 genetic variants and blood dose-adjusted trough concentrations （C0/D） of Tac at 1st month at the beginning of the immunosuppressive therapy was evaluated in cohorts of 113 patients,then at 1st,3rd,6th,and 12th months after transplantation in 41 patients who received Tac-based immunosuppressive therapy and never changed within one year after transplantation,respectively.In addition,we also evaluated the association between CYP3A5 genetic variants and other clinical outcomes,such as the classifications of endomyocardial biopsy and longterm prognosis.Results The CYP3A5 wild homozygote （＊ 1/＊ 1）,mutant homozygote （＊ 3/＊ 3）,and mutant heterozygote （＊ 1/＊ 3） occurred in 5,34 and 74 recipients respectively.The gene mutation rate of CYP3A5 in this cohort of Chinese HTx recipients was 80.5 % and the homozygous proportion was 65.5%.Compared with CYP3A5 expressors （＊ 1/＊ 1 or ＊ 1/＊ 3）,CYP3A5 nonexpressors （＊ 3/＊ 3） had a higher Tac C0/D at 1st month （47.34 ± 11.40 vs.116.11 ± 42.40 vs.293.70 ± 171.20,P =0.000）,as well as other studied time points （3rd month：98.32 ± 39.43 vs.292.07 ± 141.08,P=0.003;6th month：90.00 ± 21.31 vs.341.68 ± 165.02,P =0.002;and 12th month：96.02 ± 29.33 vs.339.23 ± 162.30,P =0.018）;and might have a lower classification of endomyocardial biopsy at 1st month （1.43 ± 0.73 vs.1.50 ± 0.58,P =0.867）,3rd month （1.55 ±1.00 vs.2.00 ± 1.73,P =0.512）,and 6th month （1.36 ± 0.84 vs.2.33 ± 1.53,P =0.132）;as well as a higher mortality due to acute organ rejection （10% vs.0,P =0.244） and all-cause mortality （20% vs.9.7%,P =0.580）.Conclusion In Chinese HTx recipients,the frequency of this ＊ 3 allele is lower than that has been reported in the white population.The determinations of CYP3A5 genetypes in he

关 键 词：心脏移植 CYP3A5 基因多态性 他克莫司 血药浓度 

分 类 号：R654.2[医药卫生—外科学]