背景:加纳慢性肾病(CKD)和肾衰竭的负担正在上升,CKD的患病率估计为13.3%。进展为肾衰竭的CKD患者需要维持生命的肾脏替代疗法(KRT),这在加纳几乎完全可以作为血液透析使用。肾移植由于其相对成本效益以及在生存和生活质量方面的优势,被认为是治疗不可逆肾衰竭患者的最佳KRT选择。然而,因为移植可能会引发潜在的器官排斥反应,免疫抑制剂如他克莫司剂量是必需的。
目的:本研究旨在确定CYP3A5、CYP3A4和MDR1基因中影响他克莫司在加纳肾衰竭患者人群中的药代动力学的单核苷酸多态性。
方法:这项横断面研究包括82名肾衰竭患者,他们在Korle-Bu教学医院(KBTH)的肾透析病房接受维持性血液透析。收集临床和人口统计学数据并分离基因组DNA。使用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)对样品的特定SNP进行基因分型。
结果:参与者,58/82(70.73%)携带野生型CYP3A5*1/*1AA基因型,20/82(24.39%)携带杂合CYP3A5*1/*3AG基因型,4/82(4.88%)具有纯合突变体CYP3A5*3/*3GG基因型。此外,6/82(7.32%)携带野生型AA基因型,11/82(13.41%)具有杂合子AG基因型,65/82(79.27%)具有CYP3A4*1B纯合突变GG基因型(-290A>G)。对于MDR1_Ex21(2677G>T),81/82(98.78%)携带野生型GG基因型,1/82(1.22%)具有杂合GT基因型。对于MDR1_Ex26(3435C>T),63/82(76.83%)具有野生型CC基因型,而18/82(21.95%)携带杂合CT基因型,1/82(1.22%)具有突变的TT基因型。
结论:描述了加纳肾衰竭患者人群中CYP3A4,CYP3A5和MDR1基因中的SNP。特征基因的不同SNP表明,在移植和他克莫司治疗之前,需要考虑加纳肾衰竭患者的遗传状态。
BACKGROUND: The burden of chronic kidney disease (CKD) and kidney failure in Ghana is on the ascendency, with the prevalence of CKD estimated at 13.3%. Patients with CKD who progress to kidney failure require life sustaining kidney replacement therapy (KRT) which is almost exclusively available in Ghana as haemodialysis. Kidney transplantation is considered the best KRT option for patients with irreversible kidney failure due to its relative cost efficiency as well as its superiority in terms of survival and quality of life. However, because transplants may trigger an immune response with potential organ rejection, immunosuppressants such as tacrolimus dosing are required.
OBJECTIVE: This
study sought to determine single nucleotide polymorphisms in CYP3A5, CYP3A4 and
MDR1 genes that affect the pharmacokinetics of Tacrolimus in a population of Ghanaian patients with kidney failure.
METHODS: This cross-sectional
study comprised of 82 kidney failure patients undergoing maintenance haemodialysis at the Renal and Dialysis unit of Korle-Bu Teaching Hospital (KBTH). Clinical and demographic data were collected and genomic DNA isolated. Samples were genotyped for specific SNPs using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP).
RESULTS: Participants, 58/82 (70.73%) harbored the wildtype CYP3A5*1/*1 AA genotype, 20/82 (24.39%) carried the heterozygous CYP3A5*1/*3 AG genotype, and 4/82 (4.88%) had the homozygous mutant CYP3A5*3/*3 GG genotype. Also, 6/82 (7.32%) carried the wildtype AA genotype, 11/82 (13.41%) had the heterozygous AG genotype, and 65/82 (79.27%) harbored the homozygous mutant GG genotype of CYP3A4*1B (-290 A>G). For MDR1_Ex21 (2677 G>T), 81/82 (98.78%) carried the wildtype GG genotype, while 1/82 (1.22%) had the heterozygous GT genotype. For MDR1_Ex26 (3435 C>T), 63/82 (76.83%) had the wildtype CC genotype, while 18/82 (21.95%) carried the heterozygous CT genotype, and 1/82 (1.22%) harbored the mutant TT genotype.
CONCLUSIONS: SNPs in CYP3A4, CYP3A5, and
MDR1 genes in a population of Ghanaian kidney failure patients were described. The varying SNPs of the featured genes suggest the need to consider the genetic status of Ghanaians kidney failure patients prior to transplantation and tacrolimus therapy.