与免疫抑制剂药代动力学和不良反应相关的遗传变异在 DeKAF 基因组全基因组关联研究中的分析。
Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies.
机构信息
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN.
Department of Biostatistics, University of Minnesota, Minneapolis, MN.
出版信息
Transplantation. 2019 Jun;103(6):1131-1139. doi: 10.1097/TP.0000000000002625.
BACKGROUND
The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.
METHODS
We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.
RESULTS
Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified.
CONCLUSIONS
These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.
背景
免疫抑制剂他克莫司和霉酚酸酯是器官移植成功的重要组成部分，但也与不良反应相关，如肾毒性、贫血、白细胞减少和移植后新发糖尿病。在本报告中，我们试图确定与这些不良反应相关的遗传变异。
方法
我们进行了一项全基因组关联研究，使用专门针对移植结局的基因分型阵列，该阵列包含 722077 个单核苷酸多态性，以及 2 个肾移植受者队列——一个发现队列和一个验证队列，以识别并验证与免疫抑制剂药代动力学和不良反应相关的遗传变异。
结果
发现了几个与他克莫司谷浓度相关的遗传变异。虽然鉴定出了一些提示性变异，但我们没有确认与其他测试表型相关的变异。
结论
这些结果表明，与他克莫司和霉酚酸酯相关的不良反应是复杂的，受者的风险不是由少数具有较大影响的遗传变异决定的，而是可能由许多具有较小效应的遗传变异和临床因素决定的。
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