Table_1_Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function.XLSX

After liver transplantation, the liver function of a patient is gradually restored over a period of time that can be divided into a convalescence period (CP) and a stabilizing period (SP). The plasma concentration of tacrolimus, an immunosuppressant commonly used to prevent organ rejection, varies as a result of variations in its metabolism. The effects of genetic and clinical factors on the plasma concentration of tacrolimus appear to differ in the CP and SP. To establish a model explaining the variation in tacrolimus trough concentration between individuals in the CP and SP, we conducted a retrospective, single-center, discovery study of 115 pairs of patients (115 donors and 115 matched recipients) who had undergone liver transplantation. Donors and recipients were genotyped by a genome-wide association study (GWAS) using an exome chip. Novel exons were identified that influenced tacrolimus trough concentrations and were verified with bootstrap analysis. In donors, two single-nucleotide polymorphisms showed an effect on the CP (rs1927321, rs1057192) and four showed an effect on the SP (rs776746, rs2667662, rs7980521, rs4903096); in recipients, two single-nucleotide polymorphisms showed an effect in the SP (rs7828796, rs776746). Genetic factors played a crucial role in tacrolimus metabolism, accounting for 44.8% in the SP, which was higher than previously reported. In addition, we found that CYP3A5, which is known to affect the metabolism of tacrolimus, only influenced tacrolimus pharmacokinetics in the SP.

在肝移植术后，患者的肝功能会在一段可划分为康复期（CP）和稳定期（SP）的时期内逐渐恢复。免疫抑制剂他克莫司的血浆浓度，该药物常用于预防器官排斥，由于其代谢过程的变异而发生变化。遗传和临床因素对康复期和稳定期他克莫司血浆浓度的影响似乎存在差异。为了建立一个解释康复期和稳定期个体间他克莫司血药谷浓度变化的模型，我们开展了一项回顾性、单中心、发现性研究，纳入了115对肝移植患者（115名供体和115名匹配的受体）。供体和受体通过全基因组关联研究（GWAS）使用外显子芯片进行基因分型。通过自举分析验证了影响他克莫司血药谷浓度的新的外显子。在供体中，两个单核苷酸多态性（rs1927321、rs1057192）对康复期有影响，四个（rs776746、rs2667662、rs7980521、rs4903096）对稳定期有影响；在受体中，两个单核苷酸多态性（rs7828796、rs776746）对稳定期有影响。遗传因素在他克莫司代谢中发挥了关键作用，在稳定期中占比高达44.8%，高于以往报道。此外，我们还发现，已知会影响他克莫司代谢的CYP3A5基因，仅影响稳定期他克莫司的药代动力学。