CYP3A4和CYP3A5基因多态性对汉族肾移植患者他克莫司血药浓度的影响

Effect of CYP3A4 and CYP3A5 Gene Polymorphisms on Tacrolimus Plasma Concentration in Renal Transplanted Recipients in the Han Population

目的:研究CYP3A4*18B(rs2242480)、CYP3A5 6989A/G(rs776746)两个位点的基因多态性对肾移植术后他克莫司血药浓度/校正剂量比值(C/D)的影响,对肾移植患者基因导向的他克莫司个体化给药提供有意义的信息和数据。方法:101名健康志愿者和56例亲体肾移植且随访超过6个月的患者参加本研究,应用基因芯片法检测2个位点的基因型。用均相酶扩大免疫分析法(EMIT)测定术后7 d、14 d、1个月、3个月和6个月时血药浓度。比较不同基因型间他克莫司C/D值之间的差异。结果:在101例汉族人群中,CYP3A4、CYP3A5的等位基因频率分别为:23.75%、73.80%。移植术后6个月内,CYP3A5 GG型(*3/*3)的C/D值显著高于AA型(*1/*1)和AG型(*1/*3)(P<0.05)。CYP3A5 AA型与AG型相比较,差异无统计学意义(P>0.05)。CYP3A4 CC型(*1/*1)的C/D值显著高于CT型(*1/*18B)和TT型(*18B/*18B)(P<0.05),其中CT型与TT型比较,C/D值差异无统计学意义(P>0.05)。结论:肾移植患者术后服用他克莫司C/D值与CYP3A4、CYP3A5基因多态性具有显著相关性。

Objective： To explore the relevance between the polymorphisms of CYP3A4 ＊ 18B（rs2242480）and CYP3A5 6989A/ G （rs776746） and the ratio of blood concentration/dosage in kidney transplanted patients treated by tacrolimus（FK506） , and provide valuable information and data for personalized FK506 administration in kidney transplanted patients by genetic technology. Method： Totally 101 healthy volunteers and 56 patients receiving parental kidney transplantation with above 6-month follow-up were recruited, and gene chips were used to detect the genotype of CYP3A4 ＊ 18B and CYP3A5 6989A/G. FK506 trough concentration of 56 patients was detected by enzyme multiplies immunoassay technique （EMIT） on the 7th, 14th and 30th day, and in the 3rd and 6th month after the surgery. The relevance between the ratio of trough concentration / dosage and polymorphisms was analyzed. Result： In 101 Han population, the allele frequency of CYP3A4 and CYP3A5 genetic variants was 23.75% and 73.80%, respectively. The single nucleo- tide polymorphism （SNP） of CYP3A5 was relevant to the ratio of blood concentration/dosage in kidney transplanted patients. After 6 months of the surgery, the blood concentration/dosage of homozygous mutant CYP3A5 GG （ ＊ 3/＊ 3 ） showed significant difference with that of homozygous wild type AA（ ＊ 1/＊ 1 ） and heterozygous mutant AG（ ＊ 1/＊ 3） （P 〈0.05 ） , and there was no significant difference between CYP3A5 AA and CYP3A5 AG. The SNP of CYP3A4 ＊ 18B was relevant to FK506 blood concentration/dosage ratio in the kidney transplanted patients ,the blood concentration/dosage of homozygous wild type CYP3A4 CC showed significant difference with that of homozygous mutant qT and heterozygous mutant CT（ P 〈 0.05 ）, and there was no significant difference between CT and TY. Conclusion： The study shows that the FK506 blood concentration/dosage ratio is relevant to the SNP of CYP3A4 and CYP3A5.