摘要
第一部分：MDR1、CYP3A4与CYP3A5基因多态性对环孢素药动学的影响
背景与目的：
肾脏移植是终末期肾病的首要选择,在过去的几十年中,肾移植受体和移植物的存活率有了显著提高,这主要归功于高效免疫抑制剂,特别是环孢素A(cyclosporine A,CsA)在肾移植中合理应用。但CsA具有个体间及个体内药代动力学差异大、治疗窗窄的特点,临床上需要对其进行血药浓度监测,从而降低排斥反应及不良反应的发生,提高移植肾的存活率。CsA是P450酶系CYP3A (Cytochrome P4503A, CYP3A)和转运蛋白P-糖蛋白(P-glycoprotein, P-gp)的底物,CYP3A基因及P-糖蛋白的编码基因多药耐药(Multidrug resistance1,MDR1)基因具有多态性。我们推测其多态性可能是导致CsA药动学个体差异的原因之一。本研究的目的即是考察CYP3A4*1G、CYP3A5*3和MDR1基因多态性对中国肾移植患者术后不同时间CsA药动学的影响。
方法：
选取以CsA+吗替麦考酚酯+糖皮质激素为基础免疫抑制剂治疗的132例中国汉族肾移植患者。采用聚合酶链反应—限制性片段长度多态性(Polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)测定患者MDR1C1236T、G267TT/A, C3435T基因型,聚合酶链反应—连接酶检测反应(Polymerase chain reaction-ligase detection reaction, PCR-LDR)测定患者CYP3A4*1G及CYP3A5*3基因型。CsA全血谷浓度(服药前浓度,C0)及峰浓度(服药后2小时浓度,C2)采用荧光偏振免疫分析法测定,并以CsA浓度/(日剂量/体重)为校正浓度,采用单因素分析法(ANOVA或Kruskal-Wallis H检验)和多元线性回归法,考察基因多态性及性别、随访年龄、红细胞比容(hematocrit,HCT)、血清肌酐(serum creatinine, Scr)、血清谷丙转氨酶(alanine transaminase,ALT)、血清白蛋白(serum albumin, ALB)等临床混杂因素对肾移植患者术后不同时间(术后0-7天、8-15天、16-30天、2-12个月及1年以上)CsA校正浓度的影响。
结果：
1.基因型分布情况
132例肾移植患者中,MDR11236T、MDR12677T、MDR12677A、MDR13435T.CYP3A4*1G和CYP3A5*3的频率分别为64.8%、39.4%、15.5%、37.5%、22.3%及74.2%。连锁分析显示CYP3A4*1G与CYP3A5*3存在较高程度的连锁,D’值为0.83,其他位点之间连锁程度较低。CYP3A4*1G与CYP3A5*3单倍体构建的结果显示：GG型为71.5%,AA型为19.5%,而AG和GA型分别为2.8%和6.2%。
2.单位点分析
单因素分析显示MDR1C1236T与移植术后8-15天CsA的谷浓度及术后1年以上的峰浓度及谷浓度相关。MDR1G2677T/A与移植术后1年以上峰浓度及谷浓度相关。MDR1C3435T则与术后16-30天的峰浓度及术后1年以上峰谷浓度相关。CYP3A4*1G影响移植术后1个月以后峰浓度及谷浓度。CYP3A5*3与术后1个月以后的峰谷浓度相关。
应用多重线性回归的方法,考察引入多个临床协变量后,基因多态性对CsA浓度的影响。结果与单因素分析有较大差别,MDR1C1236T与移植术后1-15天CsA的谷浓度及术后1年以上的峰浓度相关。MDR1G2677T/A与移植术后1年以上峰浓度及术后16天至1年的谷浓度相关。MDR1C3435T则与术后16-30天和1年以后的谷浓度以及8-30天的峰浓度相关。CYP3A4*1G影响移植术后1年以后的谷浓度以及8天以后的峰浓度。CYP3A5*3只与术后1年以后的谷浓度相关。结果总结见表2。
表1基因多态性对CsA血药浓度的影响(多重回归分析结果总结)
3. CYP3A4/5联合分析
CYP3A4*1G-CYP3A5*3联合基因型影响患者术后1年以后校正谷浓度与峰浓度,亦影响术后1年以内的峰浓度,结果总结见表2。CYP3A4/5AA-AA型患者校正浓度低于GG-GG型患者：术后1年以后,GG-GG型的谷浓度平均为28.67mg/ml,而AA-AA型为8.19mg/ml,较GG-GG型低约70%;GG-GG型的峰浓度平均为202.10mg/ml,而AA-AA型为127.65mg/ml,较GG-GG型低约37%。但多重线性回归分析显示各模型校正R平方均<20%,因此可解释总变异的比例较低。
表2CYP3A4/5联合基因型对CsA血药浓度的影响
4. MDR1与CYP3A联合分析
采用多重线性回归,分析CYP3A4/5联合基因型与MDR1联合基因型对CsA血药浓度的共同影响。CYP3A4/5联合基因型与MDR1联合基因型进入同一回归模型中。结果显示CYP3A4/5影响术后1个月以后的峰浓度及谷浓度,与1个月以内的谷浓度亦呈相关性。而MDR1只影响移植术后1年以后的谷浓度,结果总结见表3。多重线性回归模型显示,在术后1年以后,MDR1与CYP3A4/5基因总变异可解释CsA谷浓度个体间总变异的36.3%,峰浓度的12.9%。
表3MDR1及CYP3A4/5联合基因型对CsA血药浓度的共同影响
5.非遗传学因素对CsA代谢的影响
年龄、HCT.ALT.Scr分别在不同的时间影响CsA的谷浓度与峰浓度。ALB与性别因素对CsA的浓度影响相对较小。
结论：
CYP3A4*1G与CYP3A5*3影响CsA的谷浓度及术后1个月以后的峰浓度,MDR1只对移植术后稳定期(1年以后)的谷浓度有影响,对峰浓度没有影响。MDR1与CYP3A4/5单独都难以解释CsA浓度个体差异,但MDR1与CYP3A4/5共同遗传变异可解释肾移植术后1年以后CsA谷浓度个体差异的36.3%,峰浓度的12.9%。肾移植术后CsA浓度个体差异的原因不仅与遗传变异有关,还受到年龄、红细胞比容和肝肾功能等非遗传因素的影响。本研究结果在一定程度上可解释肾移植术后CsA浓度个体间差异的原因。
第二部分：MDR1、CYP3A4、CYP3A5及FOXP3基因多态性对环孢素药效学的影响
背景与目的：
CsA不仅药动学个体差异大,药效学亦表现出较大的个体差异,即相同的血药浓度可能会导致不同的药物效应。目前,临床上主要对CsA血药浓度进行治疗药物监测,并探索药物转运蛋白及相关代谢酶遗传多态性对其药动学的影响,较少对其药效学及影响因素的评价和监测。本研究在考察CYP3A4*1G、 CYP3A5*3和MDR1C1236T、G2677T/A、C3435T多态性对CsA药动学的影响的基础上,进一步探索其对CsA药效学的影响。
CsA通过抑制IL-2的产生,不仅抑制辅助性T细胞的活化,而且抑制了调节性T细胞(regulatory T cell,Treg)。FOXP3是Treg的管家基因,其表达与Treg的功能及肾移植患者排斥反应相关。FOXP3基因具有多态性,其中启动子区域的rs3761547(-3499A/G)、rs3761548(-3279A/C)与rs2232365(-924A/G)在中国人中有较高的突变频率。多项研究证明FOXP3基因突变与一些自身免疫性疾病的发病相关。但FOXP3基因多态性对肾移植患者CsA免疫抑制效应的影响,目前国内外尚未见文献报道。
因此,本部分研究的目的即是：探索CYP3A4*1G、CYP3A5*3、MDR1(C1236T.G2677T/A和C3435T)以及FOXP3(rs3761547、rs37615483和rs2232365)基因多态性对中国肾移植患者CsA免疫抑制效应(预防排斥反应)的影响。
方法：
131例接受CsA+吗替麦考酚酯+糖皮质激素作为基础免疫抑制治疗的中国汉族肾移植患者,根据排斥反应发生与否,分为排斥组(58例)和未排斥组(73例)。所有排斥反应,均经过肾穿刺后病理证实,根据Banff05分级,分为抗体介导的急性排斥反应,T细胞介导的急性排斥反应、抗体介导的慢性排斥反应、T细胞介导的慢性排斥反应。FOXP3rs3761547、rs3761548与rs2232365基因型采用Taqman探针法测定。采用Binary logistic回归比较不同基因型患者移植术后1年、2年、3年及5年的移植排斥发生率。应用Kaplan-Meier分析及log-rank检验进行事件史分析(生存分析),移植术后第一次排斥反应被定义为事件,发生时间定义为生存时间。Cox回归分析考察基因变异及临床非基因组因素(包括CsA浓度、年龄、性别、身高、诱导治疗及器官来源)对患者总排斥率的影响。进一步采用Kaplan-Meier分析考察基因变异对急性T细胞介导排斥反应发生的影响(移植术后第一次急性T细胞介导排斥反应,定义为事件)。
结果：
1.基本资料及CsA血药浓度
排斥组和未排斥组患者年龄、性别、体重、身高、冷缺血时间、是否应用诱导治疗、器官来源(尸体供肾或活体供肾)及术后1个月、1年、2年、3年和5年的CsA血药浓度,均无明显差异。
2.基因型分布
在131例中国汉族肾移植患者中,FOXP3基因rs3761547G、rs3761548C和rs2232365G的发生频率分别为13.4%、83.6%和24.8%。连锁分析显示rs3761547与rs3761548, rs3761547与rs2232365, rs3761548与rs2232365之间,D’分别为0.99,0.96和0.57。rs3761547-rs3761548-rs2232365单倍体频率：ACA型为70.2%,GCG型为13.0%,AAG型为11.8%,AAA和GCA分别为4.6%和0.4%。
3. Binary logistic回归分析
在肾移植术后1年、2年、3年及5年内,分别有41例、52例、54例和55例患者发生了排斥反应,另外有3例患者在移植术后5年以后发生了排斥反应。CYP3A4*1G、CYP3A5*3、MDR1基因C1236T、G2677T/A、C3435T及FOXP3基因rs3761547、rs2232365不同基因型患者排斥发生率,无显著性差异(P>0.05)。而rs3761548的多态性则对肾移植排斥发生率有显著影响。在术后1年内,携带有rs3761548AA型患者,发生排斥的概率是CC患者的3.79倍(95%CI：1.11-12.95,P=0.034),术后2年内,AA型是CC型的5.82倍(95%CI：1.48-15.93,P=0.012),术后3年内,AA型是CC型的5.33倍(95%CI：1.36-14.97,P=0.017),术后5年内,AA型是CC型的5.11倍(95%CI：1.30-14.07,P=0.019)。
4. Kaplan-Meier及Cox回归分析
Kaplan-Meier分析显示rs3761548对肾移植排斥反应的发生有显著影响,AA型患者肾移植术后发生首次排斥反应的时间要早于CC型患者(Logrank=6.952, P=0.031), AA型与CC型患者发生排斥反应的时间分别是术后35.71±14.50月和73.18±6.00月。应用Cox比例风险模型显示,在引入其他各混杂因素后,rs3761548多态性依然显著影响肾移植排斥反应的发生(HR2.70,95%CI1.22-5.96,P=0.014)。联合基因型分析显示3761547-3761548AA-AA型患者发生排斥反应的风险比是AG-CC型患者的2.83倍(95%CI1.22-6.58,P=0.016)。而CYP3A4、 CYP3A5、MDR1及FOXP3rs3761547、rs2232365多态性对肾移植排斥反应的发生没有显著影响。非基因组因素对排斥发影响无统计学意义。
以急性T细胞介导排斥反应作为终点事件,进行Kaplan-Meier分析,结果显示只有rs3761548多态性与急性T细胞介导的排斥发生密切相关(Log Rank=7.853,P=0.020),而CYP3A4*1G、CYP3A5*3、MDR1及FOXP3rs3761547与rs2232365,均对急性T细胞介导的排斥发生无显著影响。结论：
CYP3A4*1G、CYP3A5*3、MDR1(C1236T、G2677T/A、C3435T)及FOXP3(rs3761547及rs2232365)多态性对CsA抑制排斥反应无明显影响,而FOXP3rs3761548位点的基因多态性与CsA抑制排斥反应的疗效密切相关。在给予CsA进行基础治疗的中国汉族肾移植患者中,rs3761548AA型患者比CC患者更容易发生排斥反应,AA型患者可能需要更强效的免疫抑制方案来预防排斥反应的发生。
PART I Association of MDR1, CYP3A4*1G and CYP3A5*3genetic polymorphisms with the pharmacokinetics of cyclosporine A in Chinese renal transplant recipients
Background and Objective
Renal transplantation is the preferred treatment of choice for most patients with end stage renal failure. The recent advent of novel immunosuppressive agents, especially cyclosporine A (CsA), has significantly improved the clinical outcome of renal transplant recipients. CsA is characterized by a narrow therapeutic index and high interindividual pharmacokinetic variations. Monitoring CsA blood levels is therefore highly recommended to improve the efficacy and reduce the toxicity of CsA treatment. CsA is a substrate of both P-glycoprotein (P-gp) and Cytochromes P4503A (CYP3A). The CYP3A and MDR1gene, encoding the P-gp, are polymorphic and we speculate these polymorphisms may contribute to CsA interindividual variance. Therefore, this study is to retrospectively evaluate the effects of MDR1, CYP3A4*1G and CYP3A5*3genetic polymorphisms on CsA pharmacokinetics in Chinese renal transplant patients during different post-transplant periods.
Methods
A total of132Chinese renal transplant patients of Han ethnicity, receiving CsA, mycophenolate mofetil and prednisolone as immunosuppression regimen, were enrolled. The genotypes of MDR1C1236T, G2677T/A and C3435T were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP); and the genotypes of CYP3A4*1G and CYP3A5*3were determined using polymerase chain reaction-ligase detection reaction (PCR-LDR). The predose and two hour postdose concentrations of CsA (Co and C2, respectively) were determined by fluorescence polarization immunoassay. Dose-adjusted Co and C2were calculated by dividing the Co and C2by the corresponding24-hour dose on a mg/kg basis. The relationships of dose-adjusted Co and C2with corresponding genotypes and haplotypes in different post-transplant periods (day0-7, day8-15, day16-30, Month2to12and after one year) were investigated using ANOVA (or Kruskal-Wallis H test) and multiple linear regression. The influence of investigated polymorphisms and other clinical variables, such as age, gender, hematocrit (HCT), serum creatinine (Scr), Alanine transaminase (ALT) and serum albumin (ALB), was determined by multiple linear regression.
Results
1. Single nucleotide polymorphisms (SNPs) among transplant patients
The frequencies of MDR11236T,2677T,2677A, C3435T, CYP3A4*1G and CYP3A5*3in132renal transplant patients were64.8%,39.4%,15.5%,37.5%,22.3%and74.2%, respectively. There was a strong linkage disequilibrium between CYP3A4*1G and CYP3A5*3(D'=0.83) and low linkage disequilibrium between other SNPs. Construction of haplotypes (CYP3A4*1G-CYP3A5*3) via expectation maximization resulted in four haplotypes and the frequencies of the CYP3A4*1G-CYP3A5*3haplotypes were71.5%for GG,19.5%for AA,6.2%for GA, and2.8%for AG, respectively.
2. Analysis of each SNPs
Univariate analysis showed that MDR1C1236T was associated with the Co of day8to15and affected the Co and C2after one year post-transplant. MDR1G2677T/A was associated with the Co and C2after one year post-transplant. MDR1C3435T was associated with the C2during day16to30and the Co and C2after one year post-transplant. Both CYP3A4*1G and CYP3A5*3were associated with the Co and C2after one month post-transplant.
We further investigated the association between each SNP and CsA dose-adjusted concentrations using multiple linear regression, when including clinical covariates. The results suggested that MDR1C1236T was associated with the Co during day1to15and C2after one year post-transplant. MDR1G2677T/A was associated with the Co during day16to one year and with C2after one year post-transplant. MDR1C3435T was related to the Co during day16to30and after one year, and also affected the C2during day8to30. CYP3A4*1G had an impact on the Co after one year and C2after8days post-transplant, while CYP3A5*3was only related to Co after one year. The results of multiple linear regression were summarized in Table1. Table1Association between each SNP and CsA dose-adjusted concentrations (multiple linear regression)
3. Analysis of combined CYP3A4*1G and CYP3A5*3
Combined CYP3A4*1G and CYP3A5*3genotype was associated with C2post-transplant and Co after one year post-transplant. The results were summarized in Table2. Patients with AA-AA genotype have a lower dose-adjusted concentration compared to those with GG-GG genotype, while the resulting model explained only <20%of the total variation. Table2Effect of combined CYP3A4*1G and CYP3A5*3genotype on CsA dose-adjusted concentrations
4. Combined analysis of CYP3A4/5and MDR1To investigate the potential interaction of CYP3A5, CYP3A4and MDR1, multiple linear regression was applied. CYP3A4/5combined genotype and MDR1combined genotype were added into the same regression model to investigate their effect on CsA concentrations. The results presented here showed that CYP3A4/5combined genotype affected CsA dose-adjusted Co and C2after1month post-transplant and Co during the first month post-transplant. MDR1combined genotype was only associated with dose-adjusted Co after1year post-transplant. The results were summarized in Table3. Combined genetic variation of CYP3A4/5and MDR1could explained36.3%of the total variance of CsA Co and12.9%of CsA C2after one year post-transplant.
Table3Effect of combined CYP3A4/5genotype and combined MDR1genotype on CsA dose-adjusted concentrations
5. The effect of non-genetic factors on CsA concentrations
Age, HCT, ALT and Scr were found to related to CsA dose-adjusted Co and C2in different post-transplant periods. ALB and gender had a relatively minor effect on the concentration of CsA.
Conclusion
The data suggested that the CYP3A4*1G-CYP3A5*3combined genotype affected CsA dose-adjusted trough and peak concentration after1month post-transplant and CsA dose-adjusted trough concentration during the first month post-transplant. Patients with CYP3A4*1G-CYP3A5*3AA-AA genotypes may require higher doses of CsA to reach the target levels. MDR1C1236T-G2677T/A-C3435T combined genotype was associated with steady-state CsA dose-adjusted trough concentration after1year post-transplant. Although MDR1and CYP3A4/5could not explain the individual variance of CsA concentrations alone, combined genetic variation of CYP3A4/5and MDR1could explain36.3%of the total variance of CsA Co and12.9%of CsA C2after one year post-transplant. Interindividual differences in CsA concentrations in Chinese transplant patients were not only related to metabolism-associated genetic variation, but also affected by non-genetic factors, such as age, HCT, liver and kidney function. The results of this study could explain the individual differences of CsA concentration of the renal transplant recipients to a certain extent.
PART Ⅱ Association of MDR1, CYP3A4*1G, CYP3A5*3and FOXP3genetic polymorphisms with the pharmacodynamics cyclosporine A in Chinese renal transplant recipients
Backgroud and Objective
CsA is characterized by high interindividual variations, not only in pharmacokinetics but also in pharmacodynamics, which means that the same plasma concentration may lead to different drug effects. At present, CsA is monitored mainly by determining drug blood levels and exploring the effects of the polymorphisms of drug transporters and metabolic enzyme on the CsA pharmacokinetics, while pharmacodynamic monitoring of CsA was less conducted. Therefore, our study further explored the polymorphisms of CYP3A4*1G, CYP3A5*3, MDR1C1236T, G2677T/A and C3435T on the immunosuppressive effect of CsA on the basis of the first part of study.
CsA not only inhibit the activation of T helper cells, by inhibiting IL-2production, but also decrease CD4+CD25+Foxp3+regulatory T cell (Treg) proliferation. FOXP3gene is known to be important for the development and function of Treg, and is associated with the rejection of human kidney transplants. FOXP3gene is polymorphic and three loci in the promoter region:-3499A/G (rs3761547),-3279A/C (rs3761548) and-924A/G (rs2232365) have a relatively higher mutation rate in eastern Asians. It has been reported that some genetic variants in the FOXP3gene may contribute to the genetic susceptibility of some autoimmune diseases. However, the effect of FOXP3gene polymorphisms on immunosuppressive effect of CsA in renal transplant patients has not been reported.
This part of study was therefore conducted to retrospectively evaluate the association of CYP3A4*1G, CYP3A5*3, MDR1(C1236T, G2677T/A and C3435T) and FOXP3(rs3761547, rs3761548and rs2232365) genetic polymorphisms with the immunosuppressive effects (preventing rejection) of CsA in Chinese renal transplant patients.
Methods
A total of131Chinese renal transplant patients of Han ethnicity, receiving CsA, mycophenolate mofetil and prednisolone as immunosuppressive regimen, were categorized into either the Rejection group (58patients) or No rejection group (73 patients). Rejection, confirmed by biopsy, was classified into acute antibody-mediated rejection, acute T-cellular-mediated rejection, chronic active antibody-mediated rejection and chronic active T-cellular-mediated rejection according to the Banff05working classification criteria. A TaqMan probe technique was performed to genotype rs3761547, rs3761548and rs2232365variant alleles in the FOXP3gene. Binary logistic regression was employed to compare the rejection rates among the patients with different genotypes in the1year,2years,3years and5years post-transplant. Time-to-event analysis was performed using Kaplan-Meier estimates and log-rank tests. The first rejection was defined as an event and time of occurrence as the life time. Multivariate Cox regression analysis was further performed to calculate the hazards associated with different polymorphisms controlling potential confounders. The impact of genetic variants on acute T-cellular-mediated rejection was also analyzed using Kaplan-Meier analysis.
Results
1. Clinical characteristics and CsA concentrations
No significant difference was observed in age, gender, weight, height, cold ischemia, induction antibody therapy, graft source (deceased donor vs. living donor) and CsA concentrations of1month,1year,2years,3years and5years post-transplant between Rejection group and No rejection group.
2. SNPs among transplant patients
Of the131Chinese Han renal transplant recipients, the frequencies of FOXP3rs3761547G, rs3761548C and rs2232365G were13.4%,83.6%and24.8%, respectively. Regarding the LD of rs3761547-rs3761548, rs3761547-rs2232365and rs3761548-rs2232365. D" was0.99,0.96and0.57, respectively. Construction of haplotypes via expectation maximization resulted in five haplotypes. The frequencies of the rs3761547-rs3761548-rs2232365haplotypes were70.2%for ACA,13.0%for GCG,11.8%for AAG,4.6%for AAA and0.4%for GCA.
3. Binary logistic regression analysis
There are41,52,54and55patients with rejection during the1,2,3and5years after kidney transplantation, respectively, and three patients experienced rejection episodes beyond the five-year observation period.
There was no significant difference in the genotype frequencies of CYP3A4*1G, CYP3A5*3, MDR1C1236T, G2677T/A, C3435T, FOXP3rs3761547, rs2232365variants between patients with and without rejection history in our patient population (P>0.05). The rs3761548genotype was significantly associated with the rejection rates. The risk for allograft rejection in the rs3761548AA genotype patients was about3.79fold (95%CI1.11-12.95, P=0.034) greater than that in the CC genotype patients during the first year post-transplant. The odds ratio was5.82(95%CI1.48-15.93, P=0.012) during the two years post-transplant,5.33(95%CI1.36-14.97, P=0.017) during the three years post-transplant and5.11(95%CI1.30-14.07, P=0.019) during the five years post-transplant.
4. Kaplan-Meier and Cox regression analysis
Kaplan-Meier survival analysis showed that the rs3761548genotype was significantly associated with allograft rejection; and that patients with the rs3761548AA genotype had a shorter mean time to first rejection episode than that of the CC genotype (35.71±14.50vs73.18±6.00months, Log rank=6.952, P=0.031). The Cox regression analysis demonstrated that the rs3761548AA genotype was associated with higher allograft rejection rate compared with the CC genotype carriers (Hazard Ratio2.70,95%CI1.22-5.96, P=0.014) after controlling potential confounders. Combined rs3761547-3761548AA-AA genotype carriers had up to about a threefold (Hazard Ratio2.83,95%CI1.22-6.58, p=0.016) higher risk of allograft rejection than those with AG-CC genotype. Other investigated polymorphisms (CYP3A4, CYP3A5, MDR1and FOXP3rs3761547, rs2232365) and clinical variables were not found to influence allograft rejection.
Kaplan-Meier survival analysis of acute T-cellular-mediated rejection associated with polymorphisms suggested rs3761548polymorphism was associated to acute T-cellular-mediated rejection (Log Rank=7.853, P=0.020), while no association was found for other polymorphisms (CYP3A4*1G, CYP3A5*3, MDR1and FOXP3rs3761547,rs2232365).
Conclusion
Our study suggested an association between FOXP3rs3761548polymorphisms and allograft rejection in Chinese renal transplantation patients receiving CsA. AA genotype carriers had a higher risk of rejection than those CC genotype patients. Patients with the AA genotype may require higher dose of CsA than those CC genotype carriers to prevent rejection. Other investigated polymorphisms of CYP3A4*1G, CYP3A5*3, MDR1(C1236T, G2677T/A and C3435T) and FOXP3(rs3761547and rs2232365) were not found to be related to allograft rejection.
引文
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