多药耐药基因多态性和单倍体对肾移植患者他克莫司血药浓度的影响

目的 研究多药耐药基因(MDR1)单核苷酸多态性及单倍体对中国汉族肾脏移植人群术后稳定期与他克莫司(免疫抑制剂)血药浓度的关系.方法 用基质辅助激光吸收电离子化-飞行时间质谱技术,分析63例肾移植患者的MDR1 exon12 C1236T、exon 21 G2677T/A、exon 26 C3435T的基因型,结合其口服他克莫司12 h后血药浓度,判断两者是否存在关联.结果 MDR1 C3435T基因多态性与他克莫司血药浓度/(剂量×体表面积)具有相关性,比值由小到大顺序:野生型纯合子＜杂合子＜突变型纯合子,差异具有统计学意义(P＜0.05).MDR1 C1236T、G2677T/A及单倍体型各组之间比较均无明显差异.结论 中国汉族肾移植患者稳定期,MDR1 C3435T与他克莫司血药浓度的个体差异具有相关性.     

ABCB1基因多态性与五酯胶囊对他克莫司增效作用的相关性研究

摘 要 目的：研究五酯胶囊对他克莫司增效作用与 ABCB1基因多态性的相关性研究。方法: 通过聚合酶链反应 限制性片段长度多态性(PCR RFLP)方法测定ABCB1 1236C>T(rs1128503)、ABCB1 2677G>T/A(rs2032582)和ABCB1 3435C>T(rs1045642)基因型,使用化学发光微粒子免疫分析技术(CMIA)检测他克莫司C0。采用协方差分析考察不同组别患者他克莫司C0/D的差异。结果: 无论是单独使用他克莫司,还是他克莫司与五酯胶囊合用,ABCB1 1236C>T、ABCB1 2677G>T/A、ABCB1 3435C>T 不同基因型及单倍型组的他克莫司C0/D均无显著差异（P>0.05）。结论: 五酯胶囊对他克莫司的增效作用与ABCB1 1236C>T、ABCB1 2677G>T/A、ABCB1 3435C>T基因多态性无关。     

CYP3A5和MDR1基因型对尿毒症患者肾移植术后早期他克莫司血药浓度和肌酐水平的影响

目的 评价真实临床实践中CYP3A5(CYP3A5*3,6986A>G)及MDR1(C3435>T,G2677>T/A,C1236>T)基因多态性对尿毒症患者接受肾移植术后早期他克莫司血药浓度的影响及其最佳治疗浓度.方法 以入选2013～2017年单中心的131例首次肾移植术且术后以他克莫司为基础进行三联免疫治疗的患者...     

CYP3A5和ABCB1基因多态性对肾移植患者术后初期他克莫司剂量、浓度及肾功能的影响

目的研究CYP3A5和ABCB1基因多态性对肾移植患者术后初期他克莫司剂量、浓度以及肾功能的影响。方法以200例肾移植患者为研究对象,使用聚合酶链式反应(PCR)-限制性内切片段长度多态性(RFLP)法和测序法检测患者CYP3A5*3和ABCB1(C1236T、G2677T/A、C3435T)基因型,比较肾移植术后28 d内不同基因型患者之间他克莫司血药浓度(C)、剂量(D)、浓度剂量比(C/D)以及肾功能(血清肌酐和胱抑素C水平)的差异。结果 CYP3A5非表达组(CYP3A5*3*3型)的C和C/D在术后7、14、21和28 d均显著高于CYP3A5表达组(CYP3A5*1*1和CYP3A5*1*3型)(P <0.05,P<0.01)。ABCB1 1236基因多态性对CYP3A5表达组患者的他克莫司C、D及C/D均没有显著影响;对于CYP3A5非表达组,ABCB1 1236 CT和TT型患者他克莫司的D及C/D有显著性差异。对于CYP3A5表达组,ABCB1 3435 TT型患者他克莫司的C和D显著低于CC型和CT型患者(P <0.05);而在CYP3A5非表达组中,ABCB1 3435 TT型患者的他克莫司D显著低于CT型。对肾功能的影响:ABCB11236和2677基因型对CYP3A5表达组和非表达组肾功能均没有显著影响。对于CYP3A5非表达组,ABCB1 3435 TT型患者移植后第7或14日肌酐和胱抑素C水平显著高于CC和CT型患者(P <0.05)。结论肾移植术后初期,CYP3A5*3、ABCB1 C1236T和ABCB1 C3435T基因多态性影响他克莫司C和D,ABCB1 C3435T基因多态性对肾功能有影响。     

CYP3A5和MDR1基因多态性对中国肝移植患者他克莫司药动学的影响

目的探讨细胞色素P450酶3A5（CYP3A5）基因和多药耐药基因（MDR1）C1236T、G2677T／A、C3435T多态性对肝移植患者口服他克莫司（TAC）后体内药动学参数的影响。方法采集28例肝移植患者手术后第1周和第3周血标本,采用LC—MS／MS法检测TAC血药浓度,计算主要药动学参数。采用聚合酶链反应结合基因测序分析28例肝移植患者CYP3A5＊3和MDR1主要基因型。结果携带MDR1 3435T基因型的肝移植患者口服TAC后,药动学参数AUC0→1和ρmax明显高于3435CC型患者,而CYP3A5＊3、MDR1 C1236T和G2677T／A基因多态性对TAC的药动学参数无明显影响。结论携带MDR1 3435T基因型肝移植患者比3435CC型患者需要较高剂量才能达到目标浓度。     

CYP3A4/5、ABCB1基因单倍型与中国肾移植患者他克莫司血药谷浓度相关性的研究

目的:探讨CYP3A4*18B、CYP3A5*3、ABCB1基因单倍型对中国肾移植患者术后一月内他克莫司谷浓度(C0/D)的影响。方法:采用限制性片段长度多态性技术分析46名肾移植患者CYP3A4*18B、CYP3A5*3、ABCB1(外显子C1236T、G2677A/T、C3435T)基因型,采用酶增强免疫测定技术测定患者C0值。结果:经分析患者CYP3A4*18B、CYP3A5*3、ABCB1(C1236T,G2677A/T,C3435T)等位基因频率分别为0.304、0.707、0.554、0.478和0.304,均符合HardyWeinberg平衡。CYP3A4-3A5、G2677A/T-C3435T及C1236T-C3435T间均表现为连锁不平衡。术后8~15、16~30天内CYP3A4*18B与患者FK506 C0/D值显著相关,野生型患者C0/D值分别为杂合及突变型患者的1.34和1.67倍。CYP3A5*3基因也与患者FK506 C0/D值显著相关。突变型患者C0/D值在术后1~7、8~15及16~30天时分别为野生及杂合型患者的1.56、1.98及1.99倍。单倍型分析发现CYP3A4/5单倍型GG型携带者C0/D值较非携带者在移植术后8~15、16~30天显著性增加1.43、1.77倍。未观察到ABCB1基因多态性及单倍型对FK506血药浓度的影响。结论:仅CYP3A4/5单倍型与他克莫司C0/D值显著相关,移植前对CYP3A4/5单倍型进行检测将有利于他克莫司给药剂量的调整。     

服用他克莫司的肾移植患者ABCB1基因多态性与术后感染的相关性

目的:观察服用他克莫司(Tacrolimus)的肾移植受者ABCB1基因多态性对于术后感染发生的影响。方法:选取行肾移植手术并服用他克莫司的患者90例,根据术后是否存在感染分为感染组和对照组,检测所有患者的ABCB1基因型3435C>T,1236C>T和2677G>A/T。采用χ²检验,方差分析和独立样本T检验的方法对患者的基本临床资料进行检验。采用卡方检验比较感染组和未感染组的基因多态性频率分布差异。结果:患者C1236T,C3435T,G2677A/T等位基因频率,均符合Hardy-Weinberg平衡。感染组和非感染组患者的年龄,性别,体质量,临床诊断,吗替麦考酚酯(Mycophenolate Mofetil)的用量均没有显著性差异。2组患者的平均血药谷浓度在一年内均无统计学差异。C1236T单核苷酸多态性对肾移植术后感染发生的影响具有统计学意义(P=0.034)。G2677A/T突变的发生对肾移植术后感染发生的影响具有统计学意义(P=0.010)。结论:ABCB1基因多态性中,仅C1236T的SNP多态性与G2677A/T的突变对肾移植术后感染发生的影响具有统计学意义。     

江苏地区汉族儿童多药耐药基因3个单核苷酸多态性位点的单倍型研究

目的分析江苏汉族人群多药耐药基因-1（MDR1）的单核甘酸多态（12外显子1236C→T突变、21外显子2677G→T/A突变、26外显子3435C→T突变）及其构成的单倍型分布。方法通过多重单碱基延伸反应（SNaPshotSNP分型技术）对江苏地区170名健康儿童的MDR1C1236T、G2677T/A、C3435T的SNP位点进行基因分型,统计各基因型频率。UNPHASED软件对MDR1的SNPs（C1236T-G2677T/A-C3435T）进行单倍型分析。结果在170例儿童中,等位基因1236T、2677T、2677A、3435T频率分别为63.5%、37.4%、17.0%和35.0%。基因型频率分布符合Hardy-Weinberg平衡（HWE）,差异无统计学意义（P〉0.05）。MDR1的1236、2677、3435三个位点间（C1236T-G2677T/A-C3435T）存在连锁不平衡性,以TTT（31.8%）、TGC（25.3%）、CGC（17.7%）和CAC（16.2%）四种单倍型为主。结论江苏地区汉族人群MDR1的单核甘酸多态及单倍型分布具有自己的特点。在临床应用相关药物时,进行基因型及单倍型检测,将有助于指导临床个体化用药。     

江苏地区汉族儿童多药耐药基因3个单核苷酸多态性位点的单倍型研究

目的 分析江苏汉族人群多药耐药基因-1(MDR1)的单核甘酸多态(12外显子1236 C→T突变、21外显子2677G→T/A突变、26外显子3435C→T突变)及其构成的单倍型分布.方法 通过多重单碱基延伸反应(SNaPshot SNP分型技术)对江苏地区170名健康儿童的MDR1 C1236T、G2677T/A、C3435T的SNP位点进行基因分型,统计各基因型频率.UNPHASED软件对MDR1的SNPs(C1236T-G2677T/A-C3435T)进行单倍型分析.结果 在170例儿童中,等位基因1236T、2677T、2677A、3435T频率分别为63.5%、37.4%、17.0%和35.0%.基因型频率分布符合Hardy-Weinberg平衡(HWE),差异无统计学意义(P>0.05).MDR1的1236、2677、3435三个位点间(C1236T-G2677T/A-C3435T)存在连锁不平衡性,以TTT(31.8%)、TGC(25.3%)、CGC(17.7%)和CAC(16.2%)四种单倍型为主.结论 江苏地区汉族人群MDR1的单核甘酸多态及单倍型分布具有自己的特点.在临床应用相关药物时,进行基因型及单倍型检测,将有助于指导临床个体化用药.     

ABCB1基因多态性与肾移植患者围手术期服用他克莫司相关不良反应的相关性

目的:探讨腺苷三磷酸(ATP)结合盒转运体B1(ABCB1)基因多态性与肾移植患者围手术期服用他克莫司相关不良反应的相关性。方法:选取2014年11月-2018年3月于我院行肾移植术且术后服用他克莫司的患者170例,检测其ABCB1 C1236T(rs1128503)、ABCB1 G2677T/A(rs2032582)和ABCB1 C3435T(rs1045642)基因型。采用χ2检验比较不同基因型患者间他克莫司相关不良反应的发生率,相关不良反应包括消化道反应、肺部感染、肾功能异常、肝功能异常、血糖升高、血脂升高、白细胞降低。采用Logistic回归模型进行单位点危险度分析。应用PHASE软件分析患者上述基因的主要单倍型,并分析其主要单倍型与他克莫司相关不良反应的相关性。结果:170例患者中,ABCB1 C1236T(rs1128503)检测结果显示CC型21例(占12.3%)、CT型78例(占45.9%)、TT型71例(占41.8%);ABCB1 G2677T/A(rs2032582)检测结果显示GG型25例(占14.7%)、GA+GT型95例(占55.9%)、AA+AT+TT型50例(占29.4%);ABCB1 C3435T(rs1045642)检测结果显示CC型57例(占33.5%)、CT型82例(占48.2%)、TT型31例(占18.3%)。不同ABCB1基因型患者间消化道反应、肺部感染、肾功能异常、血糖升高、血脂升高、白细胞降低的发生率差异均无统计学意义(P>0.05),但ABCB1 C1236T(rs1128503)及ABCB1 C3435T(rs1045642)不同基因型患者间肝功能异常的发生率差异有统计学意义(P<0.05),ABCB1 G2677T/A(rs2032582)不同基因型患者间肝功能异常的发生率差异虽无统计学意义(P=0.069),但P<0.1。Logistic回归分析显示,ABCB1 C1236T(rs1128503)CC型[OR=4.959,95%CI(1.700,14.468),P=0.003]、ABCB1 G2677T/A(rs2032582)GG型[OR=3.500,95%CI(1.164,10.524),P=0.026]以及ABCB1 C3435T(rs1045642)CC型[OR=3.033,95%CI(1.012,9.095),P=0.048]均为他克莫司致相关肝功能异常的风险因子。ABCB1 CGC单倍型为主要单倍型,其携带与否与他克莫司相关肝功能异常的发生率差异存在统计学意义(P=0.002),且是他克莫司相关肝功能异常的风险因子[OR=3.173,95%CI(1.512,6.656),P=0.002]。结论:携带ABCB1 CGC单倍型的肾移植患者围手术期服用他克莫司出现肝功能异常的可能性较大。     

肾移植中环孢素的血药浓度与多药耐药基因多态性的关系

目的 探讨肾移植术后患者的MDR1C3435T、G2677T/A和C1236T位点的基因多态性对环孢素(CsA)血药浓度的影响.方法 使用荧光偏振免疫分析法(AxsYM)测定65例肾移植患者在术后1 wk和1 mo时的CsA血药浓度(包括峰浓度ρ2和谷浓度ρ0),使用等位基因特异扩增法(ASA-PCR)对患者进行MDR1基因分型,比较不同基因型之间CsA浓度剂量比的差异.结果 在65例患者中,C3435T,CC型25例(38.5%),CT型35例(53.8%),TT型5例(7.7%);G2677T/A,GG型15例(23.1%),GT型21例(32.3%),TT型10例(15.4%),GA型12例(18.5%),AT型6例(9.2%),AA型1例(1.5%);C1236T,CC型10例(15.4%),CT型32例(49.2%),TT型23例(35.4%).C3435T的CT型患者的CsA浓度剂量比略大于CC型和TT型;G2677T/A的从型患者的CsA浓度剂量比略大于其他基因型;C1236T的TT型患者的谷浓度剂量比略大于CC型和CT型,CC型患者的峰浓度剂量比略大于CT型和TT型,但差异均无统计学意义(P＞0.05).结论 在肾移植患者中,MDR1多态性与CsA血药浓度无明显相关性,有待进一步确认.     

Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem

Objective  The aim of this study was to assess the influence of the cytochrome (CYP450)3A5 and multidrug resistance (MDR1) gene polymorphisms on cyclosporine A (CsA) trough concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem. Methods   CYP3A5*3 (A6986G) and MDR1 C1236T, G2677T/A and C3435T polymorphisms were determined by PCR followed by restriction fragment length polymorphism (RFLP) analysis. A total of 112 Chinese renal transplant patients were enrolled in the study. The whole blood trough concentration was measured at 7 days after transplantation, and the dose-adjusted trough levels were compared among the different genotypes. Results  The dose-adjusted trough levels of CsA were significantly higher in MDR1 2677TT carriers than in GG plus GT carriers (59.5 ± 15.9 vs. 34.5 ± 9.4 vs. 43.2 ± 13.6 ng/mL per mg per kg; P < 0.0001). In patients who were co-treated with diltiazem, compared with carriers of haplotype T-T-C, the carriers of haplotype C-G-C and haplotype T-G-T had significantly lower dose-adjusted trough blood concentrations of CsA than the non-carrier group (P = 0.002, P = 0.000 and P = 0.000, respectively). However, no evidence was found that there was a relationship between the CYP3A5*3, MDR1 C1236T and MDR1 C3435T polymorphisms and CsA dose-adjusted trough concentrations. Conclusion  This study demonstrated that the G2677T/A single nucleotide polymorphisms in MDR1 and MDR1 haplotypes C-G-C, T-G-T and T-T-C are associated with the CsA concentration during the very early post-transplant period in Chinese renal transplant patients co-treated with diltiazem. These polymorphisms may be useful for determining the appropriate initial dose of CsA after renal transplantation.     

MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients

AIM: This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients. METHODS: Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C(0)) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined. RESULTS: No significant differences were observed between groups. Differences in mean tacrolimus C(0) values between carriers and noncarriers of each haplotype ranged from -0.04 microg/litre (95% confidence interval: -0.53 to 0.60) to -23 microg/litre (-1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions. CONCLUSION: MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.     

MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer

The genotype frequencies of MDR1 T-129C, C1236T, G2677A,T and C3435T SNPs were compared in 154 healthy Japanese and 100 healthy Caucasians to provide basic information on the inter-ethnic differences of pharmacotherapeutic outcome. The variants were found at allelic frequencies of 5.5%, 65.6%, 16.6%, 40.6% and 40.6%, for T-129C, C1236T, G2677A, G2677T and C3435T, respectively, in Japanese, and at 5.1%, 45.9%, 3.6%, 46.4% and 56.6%, respectively, in Caucasians, with a statistically significant difference for C1236T, G2677A,T and C3435T (p<0.001). G2677A was about 5-fold more frequent in Japanese than Caucasians. These genotype frequencies were also investigated in 95 Japanese patients with colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC), but no significant difference was detected, when compared with healthy Japanese subjects. The haplotype frequency reached a total of about 85% in Japanese with the following 4 major haplotypes; T(-129)-T1236-T2677-T3435 (36.1%), T(-129)-T1236-G2677-C3435 (22.5%), T(-129)-C1236-G2677-C3435 (14.2%) and T(-129)-C1236-A2677-C3435 (13.3%). The second and fourth haplotypes were hardly inferred in Caucasian, whereas T(-129)-C1236-G2677-T3435 (12.8%) was found to be Caucasian-specific. There was a tendency for higher frequencies of the T(-129)/C-(129)-C1236-A2677-C3435 haplotype in Japanese CRC patients and T(-129)-T1236-T2677-T3435 haplotype in Japanese ESCC patients, compared with that in healthy Japanese subjects.     

Analyses of single nucleotide polymorphisms and haplotype linkage of the humanABCB1 (MDR1) gene in Korean

Single nucleotide polymorphisms (SNPs) in theMDR1 gene that are responsible for drug efflux can cause toxicity. Therefore, this study determined the SNPs of the KoreanMDR1 gene, and analyzed the haplotypes and a linkage disequilibrium (LD) of the SNPs determined. The frequency of 9 SNPs from theMDR1 gene was determined by PCR-RFLP analyses of 100 to 500 healthy individuals. The frequcies of the SNPs were C3435T (47.7%), G2677T (37.6%), G2677A (4.4%), T1236C (21.7%), T129C (8%), A2956G (2.5%), T307C (1.5%), A41aG (9.2%), C145G (0%), and G4030C (0%). Analyses of the haplotype structure and an estimation of the LD of the combined polymorphisms demonstrated that the frequency of the 1236T-2677G-3435T haplotype is much higher in Koreans (14.1%) than in Chinese and western black Africans and the C3435T SNP in Koreans appears to have LD with T129C in Koreans for the first time. These results provide insight into the genetic variation ofMDR1 in Koreans, and demonstrated the possibility of a new LD in this gene.     

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

Aim:

Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered the relationship between MDR1 genetic polymorphisms and CsA concentration in Chinese patients with renal transplantation.

Methods:

A total of 126 renal transplant patients were enrolled. All the patients received CsA (2–4 mg·kg⁻¹·d⁻¹), and diltiazem (90 mg/d) was co-administered to 76 patients. MDR1-C1236T, G2677T/A, and C3435T polymorphisms were genotyped. The whole blood concentration was measured using the FPIA method, and the adjusted trough concentrations were compared among the groups with different genotypes.

Results:

In all patients, MDR1-C1236T did not influence the adjusted CsA trough concentration. With regard to MDR1-3435, the adjusted CsA trough concentration was significantly higher in TT carriers than in CC and CT carriers when diltiazam was co-administered (58.83±13.95 versus 46.14±7.55 and 45.18±12.35 ng/mL per mg/kg, P=0.011), and the differences were not observed in patients without diltiazam co-administered. With regard to MDR1-2677, the adjusted CsA trough concentration was significantly higher in TT carriers than in GG and GT carriers when diltiazam was co-administered (61.31±12.93 versus 52.25±7.83 and 39.70±7.26 ng/mL per mg/kg, P=0.0001). The differences were also observed in patients without diltiazam co-administered (43.27±5.95 versus 35.22±7.55 and 29.54±5.35 ng/mL per mg/kg, P=0.001). The adjusted CsA trough blood concentration was significantly higher in haplotype T-T-T and haplotype T-T-C carriers than in non-carriers, regardless of diltiazem co-administered.

Conclusion:

MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.     

Effects of MDR1 1236C > T-2677G > T-3435C > T polymorphisms on the intracellular accumulation of tacrolimus,cyclosporine A,sirolimus and everolimus

Abstract

1. Overexpression of P-glycoprotein (P-gp, encoded by MDR1) mediates resistance to multiple immunosuppressors. Several common MDR1 variants (1236C?>?T, 2677G?>?T, 3435C?>?T) impact the efflux activity of P-gp-mediated substrates. We assessed the effect of these polymorphisms on the sensitivity, intracellular accumulation, and efflux of tacrolimus, cyclosporine A, sirolimus and everolimus in transfected LLC-PK1 cells.

2. LLC-PK1 cell lines were transfected with empty vector (pcDNA3.1) and recombinant MDR1_T-T-T, MDR1_C-T-T, MDR1_C-G-T and MDR1_C-G-C vectors, respectively and further screened in the presence of puromycin. The IC₅₀ values, intracellular accumulation, and apparent permeability ratios of tacrolimus, cyclosporine A, sirolimus and everolimus were evaluated.

3. MDR1 overexpression increased the resistance of LLC-PK1 cells to tacrolimus, cyclosporine A, sirolimus and everolimus. The resistance of cells expressing MDR1_C-G-C wild-type haplotypes to tacrolimus were increased compared to MDR1_T-T-T, MDR1_C-T-T, MDR1_C-G-T variant haplotypes. The efflux ability of P-gp-mediated tacrolimus in cells transfected with MDR1_C-G-C was higher than cells overexpressing MDR1_T-T-T, MDR1_C-T-T, MDR1_C-G-T variant haplotypes. In addition, the resistance of cells expressing MDR1_C-G-C wild-type haplotypes to sirolimus were increased compared to MDR1_C-T-T, MDR1_C-G-T variant haplotypes. The efflux ability of P-gp-mediated sirolimus in cells overexpressing MDR1_C-G-C was higher than cells transfected with MDR1_C-T-T, MDR1_C-G-T variant haplotypes.

4. These findings indicate that wild-type MDR1 exports tacrolimus and sirolimus more efficiency than the MDR1_T-T-T, MDR1_C-T-T, MDR1_C-G-T variant protein. This observation indicates that 1236C?>?T, 2677G?>?T, 3435C?>?T variant haplotypes drastically decrease the efflux ability of P-gp-mediated tacrolimus and sirolimus in a substrate-specific manner.