Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN.
Hennepin Healthcare Research Institute, Minneapolis, MN.
Transplantation. 2019 Aug;103(8):1591-1602. doi: 10.1097/TP.0000000000002659.
Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism.
In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans.
Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4.
Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients.
识别易发生急性排斥反应 (AR) 的肾移植受者，可优化临床治疗，避免排斥反应并延长移植物存活时间。人们假设，这种易感性的一部分是由特定遗传变异的遗传引起的。有许多出版物报告了遗传变异与 AR 之间存在统计学意义上的关联，这些变异通常以单核苷酸多态性 (SNP) 的形式存在。然而，当对同一单核苷酸多态性分析不同的受者队列时，也有许多出版物报告缺乏这种关联。
在本报告中，我们试图使用包含 2390 名欧洲裔美国人和 482 名非裔美国人的大型肾移植受者队列，对之前报道与 AR 相关的 75 个常见遗传变异进行验证。
在所测试的变异中，只有一个变异 rs2910164，改变了 microRNA MIR146A 的表达，在非裔美国人队列中表现出与 AR 显著相关。在 CTLA 和 TLR4 基因中发现了提示性变异。
我们的结果表明，之前报道与 AR 相关的大多数变异在我们的队列中未得到验证。这表明在报告与 AR 等复杂临床结局相关的关联时，验证的重要性。需要进一步的研究来了解 MIR146A 在肾移植受者 AR 风险中的作用。
