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目的了解中国人群中细胞色素P4503A5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(cyclosporinA,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CYP3A53,其频率为76.1%(274/360);3种基因型,即纯合子CYP3A51/110份,占总数的5.6%;杂合子CYP3A51/366份,占总数的36.7%;纯合子CYP3A53/3104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CYP3A51/12例和CYP3A51/310例。CYP3A51/1患者外周血均一化后的CsA浓度与CYP3A51/3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2h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CYP3A53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,CYP3A51/1比CYP3A51/3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。
Objective To understand the polymorphism of cytochrome P4503A5 gene CYP3A5 and the relationship between genotype and clinical function in Chinese population. Methods The genetic variation of 180 samples was detected by denaturing high performance liquid chromatography and verified by sequencing. The blood concentration of cyclosporin A (CsA) in 12 hematopoietic stem cell transplantation patients was monitored by immunofluorescence polarization. The data were statistically analyzed Software analysis and processing. Results Among the 180 samples, one allele, CYP3A53, was detected with a frequency of 76.1% (274/360). Three genotypes (homozygous CYP3A51 / 110, accounting for 5.6% of the total), heterozygous CYP3A51 / 366, accounting for 36.7% of the total; homozygous CYP3A53 / 3104, accounting for 57.8% of the total. Two genotypes were detected in 12 hematopoietic stem cell transplant patients, CYP3A51 / 12 and CYP3A51 / 310. Compared with CYP3A51 / 3, the concentration of CsA in peripheral blood of CYP3A51 / 1 patients was lower than that of CYP3A51 / 3 by 2.3 ~ 6.6 times, the difference was statistically significant (P <0.01); the peak C2 Also lower than the latter, a difference of 1.4 to 3.8 times, the same difference was statistically significant (P <0.01). Conclusion CYP3A53 is the most predominant polymorphism in Chinese population. CYP3A5 genotype is closely related to the concentration of CsA in blood of patients with hematopoietic stem cell transplantation. CYP3A51 / 1 requires larger dose of CsA than CYP3A51 / 3 to maintain the same blood concentration. Genotyping of CYP3A5 by denaturing high performance liquid chromatography can predict the function of CYP3A5 in patients and predict its demand for CsA so that CsA is more safe, effective and individualized in clinic.