CYP3A5基因的多态性及其临床意义的研究

目的 了解中国人群中细胞色素P450 3A5基因CYP3A5的多态性及其基因型与临床功能之间的关联。方法 应用变性高效液相色谱技术对180份样本进行基因变异的检测，并经测序验证；以免疫荧光偏振技术监测12例造血干细胞移植患者环孢素（cyclospofin A，CsA）血浓度，数据经统计学软件分析和处理。结果 180份样本中，共检测出1种等位基因即CYP3A5＊3，其频率为76．1％（274／360）；3种基因型，即纯合子CYP3A5＊1／＊1 10份，占总数的5．6％；杂合子CYP3A5＊1／＊3 66份，占总数的36．7％；纯合子CYP3A5＊3／＊3 104份，占总数的57．8％。12例造血干细胞移植患者中检测出两种基因型，即CYP3A5＊1／＊1 2例和CYP3A5＊l／＊3 10例。CYP3A5＊1／＊ l患者外周血均一化后的CsA浓度与CYP3A5＊1／＊3相比较，前者谷浓度C0较后者低，相差2．3～6．6倍，差异有统计学意义（P〈0．01）；服药后2 h峰值C2亦较后者低，相差1．4～3．8倍，同样差异有统计学意义（P〈0．01）。结论 CYP3A5＊3是中国人群中最主要的多态性，CYP3A5基因型与造血干细胞移植患者血中CsA浓度紧密关联，CYP3A5＊1／＊1比CYP3A5＊1／＊3需要更大剂量的CsA以维持相同的血浓度。应用变性高效液相色谱对CYP3A5进行基因型分型，可以预测患者CYP3A5的功能，进而预测其CsA的需求量，使临床应用CsA更加安全有效和个体化。

Study on polymorphisms of CYP3A5 gene and their clinical role

OBJECTIVE: To investigate the polymorphisms of CYP3A5 gene in Chinese population and the association between CYP3A5 genotypes and their clinical functions. METHODS: CYP3A5 gene varisances were detected in 180 samples using denaturing high-performance liquid chromatography(DHPLC), and CsA concentrations in 12 of 180 samples from hemopoietic stem cell transplant recipients were monitored by a commercial fluorescence polarization immunoassay. The data were analyzed by a statistical software. RESULTS: In the 180 samples, there was only one allelic variant CYP3A5*3 with a frequency of 76.1% (274/360), and there were three CYP3A5 genotypes, namely CYP3A5*1/*1, CYP3A5*1/*3 and CYP3A5*3/*3 with frequencies of 5.6%, 36.7% and 57.8% respectively. Also, there were significant differences in CsA concentrations, including standardized trough concentrations C(0) and two-hour peak concentrations C(2), between CYP3A5 CYP3A5*1/*1 and CYP3A5*1/*3 found in 12 hemopoietic stem cell transplant recipients, and both C(0) and C(2) in CYP3A5*1/*1 were lower than those in CYP3A5*1/*3. CONCLUSION: CYP3A5*3 is the primary allelic variant in Chinese population. CYP3A5 genotypes are closely associated with blood CsA concentrations in hemopoietic stem cell transplant recipients, and CYP3A5*1/*1 requires a larger CsA dose to maintain the same blood concentration than does CYP3A5*1/*1. CYP3A5 genotyping by DHPLC may predict recipients' phenotype and CsA dose requirement.