【作者】 刘澍； 李嘉丽； 王雪丁； 王长希； 黄红兵； 黄民；

【Author】 LIU shu;LI jiali;WANG xueding;WANG changxi;HUANG hongbin;HUANG Min;Sun Yat-sen University Cancer Center,State Key Laboratory of Oncology in South China,Collaborative Innovation Center of Cancer Medicine;

【机构】 中山大学肿瘤防治中心,华南肿瘤学国家重点实验室,肿瘤医学协同创新中心； 中山大学临床药理研究所； 中山大学附属第一医院器官移植中心；

【摘要】 目的:回顾性研究细胞色素P450氧化还原酶POR基因多态性与肾移植手术后早期他克莫司全血谷浓度的相关性,探讨POR基因多态性对CYP3A介导的他克莫司体内代谢的影响,为优化他克莫司的个体化给药提供依据。方法:纳入肾移植术后服用他克莫司+霉酚酸酯+糖皮质激素的患者96例,采用PCR-RFLP法检测CYP3A5*3基因多态性,采用Sequenom MassARRAY SNP genotype analysis法检测PORA503V、POR831-35C>T、PORrs17685基因多态性,术后第七天他克莫司全血谷浓度(CO)为临床治疗药物监测(TDM)数据,采用SPSS16.0软件统计分析。结果:96例中国肾移植患者中,PORA503VCC型、CT型、TT型频率分别为53.97%、38.10%、7.93%,C等位基因频率为64.84%,T等位基因频率为35.16%。POR 831-35C>T CC型、CT型、TT型频率分别为44.57%、42.39%、13.04%,C等位基因频率为65.76%,T等位基因频率为34.24%。POR rs17685 CC型、CT型、TT型频率分别为45.05%、41.76%、13.19%,C等位基因频率为65.93%,T等位基因频率为34.07%。以上基因型均符合Hardy-Weinberg平衡。POR A503V CC、CT、TT型患者术后第七天他克莫司全血谷浓度剂量比分别为112.73±51.00、128.05±70.35、101.56±3 4.75ng/mL per mg/kg,三种基因型组间不存在统计学差异(P>0.05);POR 831-35C>T CC CT、TT型患者术后第七天他克莫司全血谷浓度剂量比分别为114.73±49.44、126.35±72.12、103.73±41.36ng/mL per mg/kg,三种基因型组间不存在统计学差异(P>0.05);POR rs17685CC、CT、TT型患者术后第七天他克莫司全血谷浓度剂量比分别为125.78±6 8.94、115.22±44.24、104.69±34.63ng/mL per mg/kg,三种基因型组间不存在统计学差异(P>0.05)。进一步的研究排除他克莫司全血谷浓度的主要影响因素CYP3A5*3基因型的影响,以CYP3A5*3基因型分层后分析发现,无论是在CYP3A5表达型者还是非表达型者中,均未发现上述三个SNP与他克莫司全血谷浓度剂量比存在相关性。讨论:应进一步纳入更多的与他克莫司转运、代谢相关的影响因子的基因多态性进行考察,确定与他克莫司全血谷浓度显著相关的SNP,为临床个体化给药提供依据。且目前研究纳入病人例数较少,需进一步扩大样本量后进行分析。更多还原

【Abstract】 Objective:Retrospectively investigated the association of POR polymorphisms with tacrolimus trough concentration in Chinese renal transplant recipients.Methods:CYP3A5~*3 polymorphisms was determined by PCR-RFLP method,PORA503 V,POR 831-350 T and POR rs17685 were detected by Sequenom MassARRAY SNP genotype analysis.Trough concentrations of tacrolimus on day 7 after renal transplantation were collected from clinical data.Statistical analysis was performed by SPSS 16.0 software.Result:Genotype frequencies of PORA503 V CC,CT and TT in 96 Chinese renal transplant recipients were 53.97%,38.10%and 7.93%,the frequencies of C allele and T allele were 64.84%and 35.16%,respectively.Genotype frequencies of P0R831-35 OT CC,CT and TT were 44.57%,42.39%and 13.04%,the frequencies of C allele and T allele were 65.76%and 34.24%,respectively.For POR rs 17685,genotype frequencies of CC,CT and TT were 45.05%,41.76%and 13.19%,the frequency of C allele and T allele were 65.93%and 34.07%,respectively.The distributions of the three genotypes were consistent with Hardy-Weinberg equilibrium.Dose-adjusted tacrolimus through concentration on day 7 were112.73±51.00,128.05±70.35 and 101.56±34.75ng/mL per mg/kg in patients carrying PORA503 V CC,CT or TT genotypes,respectively.There were no significant statistical differences among those three genotype groups(P>0.05).Dose-adjusted tacrolimus through concentration were 114.73±49.44,126.35±72.12 and103.73±41.36ng/mL per mg/kg in patients carrying POR 831-350 T CC,CT or TT genotypes,respectively.There were no significant statistical differences among those three genotype groups(P>0.05).For POR rsl7685,dose-adjusted tacrolimus through concentration werel25.78±68.94,115.22±44.24 and 104.69±34.63 ng/mL per mg/kg in patients carrying CC,CT or TT genotypes,respectively.No significant statistical differences were observed among those three genotype groups(P>0.05).Further research was carried out to exclude the influence of CYP3A5~*3 genotype,which is the major factor influencing tacrolimus through concentration.However,no significant associations were found between the three SNPs and tacrolimus concentrations in either CYP3A5 expressers or nonexpressers.Discussion:Further study with a larger sample size is needed to verify the influences of POR genetic polymorphisms on tacrolimus concentrations.More influence factors need to be researched to find out the reasons leading to the interindividual variability in tacrolimus pharmacokinetics,so as to individualize the use of tacrolimus.更多还原