Exome Sequencing and Prediction of Long-Term Kidney Allograft Function.
Exome Sequencing and Prediction of Long-Term Kidney Allograft Function.
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长期肾脏同种异体移植功能的外显子组测序和预测。
DOI：
10.1371/journal.pcbi.1005088
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发表时间：
2016-09
影响因子：
4.3
通讯作者：
Campagne F
中科院分区：
文献类型：
--
作者：
Mesnard L;Muthukumar T;Burbach M;Li C;Shang H;Dadhania D;Lee JR;Sharma VK;Xiang J;Suberbielle C;Carmagnat M;Ouali N;Rondeau E;Friedewald JJ;Abecassis MM;Suthanthiran M;Campagne F
目前改善肾移植后移植物结局的策略考虑了人类白细胞抗原（HLA）基因座的信息。细胞表面抗原，除了HLA，可以作为刺激以及抗同种异体免疫反应的目标，并影响长期移植结果。因此，我们对肾移植受者及其活体供体的DNA进行了外显子组测序，并通过计算跨膜蛋白中氨基酸错配的数量来估计给定供体/受者对的所有可能的细胞表面抗原错配。我们将该计数指定为同种异体组学错配评分（AMS）。我们使用混合模型研究了AMS与移植后估计肾小球滤过率（eGFR）之间的相关性，考虑了来自三个独立队列的移植（共53个供体-受体对，106个外显子组和239个eGFR测量值）。我们发现AMS对eGFR有显著影响（混合模型，整个评分范围内的效应量：-19.4 [-37.7，-1.1]，P = 0.0042，χ2 = 8.1919，d. f. = 1）与HLA-A、B、DR匹配、供体年龄和移植后时间无关。AMS效应在研究的三个独立队列中是一致的，并且与供体年龄的强效应量相似。总之，这些结果表明，AMS，一种新的工具，以量化跨膜蛋白在个别供体/受体对的氨基酸错配，是一个强大的，强大的预测长期移植肾功能在肾移植受体。这篇文章描述了一个新的概念，以帮助匹配供体器官的受体肾移植。这个概念依赖于测量潜在捐赠者和接受者的个体DNA的能力。当关于基因组的数据（即，DNA），本文描述了如何通过计算比较数据，以确定这些基因组中的差异，并量化这些差异对移植物功能的未来可能影响。文章中提出的概念确定了每对可能的供体和受体的分数。该评分被称为同种异体组学错配评分。该研究测试了该评分预测移植手术后数年受体移植物功能（移植物过滤血液的能力）的能力。该研究发现，在三组接受测试的患者中，该评分是移植功能的强有力预测因素。之前的研究通常认为，基因组中只有少数位置最有可能对移植功能产生影响，而这项研究发现了初步证据，表明编码大量蛋白质的DNA之间的差异可能对移植功能产生综合影响。
Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients. The article describes a new concept to help match donor organs to recipients for kidney transplantation. The concept relies on the ability to measure the individual DNA of potential donors and recipients. When the data about genomes (i.e., DNA) of possible donors and recipients are available, the article describes how data can be computationally compared to identify differences in these genomes and quantify the possible future impact of these differences on the functioning of the graft. The concept presented in the article determines a score for each pair of possible donor and recipient. This score is called the allogenomics mismatch score. The study tested the ability of this score to predict graft function (the ability of the graft to filter blood) in the recipient several years after transplantation surgery. The study found that, in three small sets of patients tested, the score is a strong predictor of graft function. Prior studies often assumed that only a small number of locations in the genome were most likely to have an impact on graft function, while this study found initial evidence that differences across DNA that code for a large number of proteins can have a combined impact on graft function.
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