MDR1 C1236T、G2677T/A、C3435T的基因多态性对中国汉族肾移植患者环孢素药动学的影响(英文)

Influence of MDR1 genetic polymorphisms on ciclosporin pharmacokinetics in Chinese renal transplant patients

目的探讨中国汉族人中肾移植患者的多药耐药基因（MDR1）外显子exon12 C1236T、exon21 G2677T／A、exon26 C3435T的单核苷酸多态性对免疫抑制剂环孢素（CsA）药动学的影响。方法采用聚合酶联反应和限制性内切片段长度多态性（PCRRFLP）的方法对89例肾移植术后的患者进行MDR1基因分型。单克隆抗体荧光免疫偏振法测定患者术后CsA的谷浓度（c0）及服药后2h浓度（c2）。比较不同基因型之间CsA浓度剂量比值的差异。结果在89例肾移植患者中，等位基因1236T、2677T、2677A、3435T突变频率分别为66％、43％、18％和37％。肾移植术后1mo内，G2677T／A基因多态性与CsA的药动学有相关性，2个等位基因都发生突变的患者，其剂量校正c0，在术后1～7d、8～15d和16～30d比野生型分别提高51％（P=0．005）、32％（P=0．002）和63％（P〈0．001）。在术后16～30d，无论携带有1个或2个突变等位基因的患者，剂量校正c2都要比野生型患者高26％（P=0．007）和19％（P=0．041）。C1236T的剂量校正c0在术后8～15d和16～30d各基因型之间差异显著，但以CC型与CT型差异最为显著，而CC型与TT型在16—30d，则差异无统计学意义（P〉0．05）。C3435T的不同基因型之间，剂量校正c0、c2差异无统计学意义（P〉0．05）。结论在中国汉族肾移植患者中，MDRI的exon12 C1236T和exon21 G26771A的单核苷酸多态性与移植术后1mo内CsA的药动学有相关性。但把这种相关性应用在在临床上，对MDR1进行遗传学检测，以优化CsA的剂量，尚待进一步的研究。

AIM To evaluate retrospectively the effects of genetic polymorphisms in exon 12 C1236T, exon 21 G2677T/A and exon 26 C3435T of MDR1 gene on ciclosporin （CsA） pharmacokinetics in Chinese adult renal transplant patients within the first month post-operation. METHODS Eight-nine renal transplant recipients receiving CsA were genotyped by the assay of polymerase chain reaction restriction fragment length polymorphism （PCR-RFLP） for the MDR1. The concentrations of CsA before （trough concentration, Co） and 2 h （peak concentration, c2） after administra- tion were determined by fluorescence polarization immunoassay. The dose per weight adjusted CsA concentrations were correlated with corresponding genotype. RESULTS The frequency of 1236T allele, 2677T allele, 2677A allele and 3435T allele in current study cohort were 66%, 43%, 18% and 37%, respectively. A correlation was found between the dose-adjusted CsA concentrations and polymorphisms in exon 21. Dose-adjusted co was higher in patients carrying twomutant alleles than those with homozygous wild-type genotype, as follows： 51% in 1 to 7 d （ P = 0.005） vs 32% during 8 to 15 d （P =0.002） vs 63% （P〈0.001） during 16 to 30 d. Dose-adjusted c2 was also higher in patients carrying one or two mutant alleles than those with homozygous wild-type genotype, as follows： 26% （ P =0.007） vs19% （ P = 0.041 ）. Regarding to exon 12, patients with CT and TT genotype had 30 % （ P = 0.002） and 18 % （ P = 0.025） lower dose-adjusted co compared to patients with CC genotype during 8 to 15 d post-transplantation, respectively, while only patients with CT genotype had lower dose-adjusted c0（36%, P =0.002） during 16 to 30 d. In addition, no evidence was found supporting a role for the C3435T polymorphism in CsA pharmacokinetics. CONCLUSION Our study in Chinese Han renal transplant patients demonstrate that a correlation existed between MDR1 exon 12 C1236T and exon 21 G2677T/A SNP and CsA pharmacokineties in the early stage after transplantation.