Novel Non-Histocompatibility Antigen Mismatched Variants Improve the Ability to Predict Antibody-Mediated Rejection Risk in Kidney Transplant.
Novel Non-Histocompatibility Antigen Mismatched Variants Improve the Ability to Predict Antibody-Mediated Rejection Risk in Kidney Transplant.
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DOI：
10.3389/fimmu.2017.01687
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发表时间：
2017
影响因子：
7.3
通讯作者：
Sarwal MM
中科院分区：
文献类型：
--
作者：
Pineda S;Sigdel TK;Chen J;Jackson AM;Sirota M;Sarwal MM
移植排斥反应是限制组织相容性抗原（HLA）不匹配器官移植后无限期生存的关键临床终点。晚期移植物丢失的主要原因是抗体介导的排斥反应（AMR），这是一个由供体特异性抗体引起的器官损伤的过程，这些抗体与HLA和非HLA（nHLA）抗原结合。AMR的诊断不完全，因为供体/受体（D/R）匹配仅限于HLA基因座，关键的nHLA免疫原性抗原仍有待鉴定。我们已经开发了一种利用D/R外显子组测序和基因表达来预测临床移植后结果的综合计算方法。我们对28例高度注释的D/R肾移植对进行了严格的统计分析，这些肾移植对具有活检证实的排斥[AMR或T细胞介导的排斥（CMR）]和无排斥（NoRej）的临床结局，确定AMR中错配的nHLA变体数量显著较高（ANOVA-p值= 0.02）。使用Fisher精确检验，我们确定了123个主要与AMR风险相关的变异（p值< 0.001）。此外，我们应用了机器学习技术来规避统计功效的问题，并且我们使用随机森林找到了65个变体的子集，这些变体预测了tx后AMR，显示出非常低的错误率。这些变体与肾脏和AMR中的排斥过程功能相关，因为它们涉及在肾脏和血管内皮中表达的基因中富集的基因和/或表达数量性状基因座（eQTL），并且是移植物排斥的免疫生物学的基础。除了目前的D/R HLA错配评估外，额外的错配nHLA D/R变体将增强甚至在器官植入之前的tx后AMR风险分层。这种创新的研究设计适用于所有实体器官移植，其中减轻AMR对移植物存活的影响可能更大，对改善人类发病率和死亡率具有相当大的益处，并为精确免疫抑制和延长tx存活打开了大门。
Transplant rejection is the critical clinical end-point limiting indefinite survival after histocompatibility antigen (HLA) mismatched organ transplantation. The predominant cause of late graft loss is antibody-mediated rejection (AMR), a process whereby injury to the organ is caused by donor-specific antibodies, which bind to HLA and non-HLA (nHLA) antigens. AMR is incompletely diagnosed as donor/recipient (D/R) matching is only limited to the HLA locus and critical nHLA immunogenic antigens remain to be identified. We have developed an integrative computational approach leveraging D/R exome sequencing and gene expression to predict clinical post-transplant outcome. We performed a rigorous statistical analysis of 28 highly annotated D/R kidney transplant pairs with biopsy-confirmed clinical outcomes of rejection [either AMR or T-cell-mediated rejection (CMR)] and no-rejection (NoRej), identifying a significantly higher number of mismatched nHLA variants in AMR (ANOVA—p-value = 0.02). Using Fisher’s exact test, we identified 123 variants associated mainly with risk of AMR (p-value < 0.001). In addition, we applied a machine-learning technique to circumvent the issue of statistical power and we found a subset of 65 variants using random forest, that are predictive of post-tx AMR showing a very low error rate. These variants are functionally relevant to the rejection process in the kidney and AMR as they relate to genes and/or expression quantitative trait loci (eQTLs) that are enriched in genes expressed in kidney and vascular endothelium and underlie the immunobiology of graft rejection. In addition to current D/R HLA mismatch evaluation, additional mismatch nHLA D/R variants will enhance the stratification of post-tx AMR risk even before engraftment of the organ. This innovative study design is applicable in all solid organ transplants, where the impact of mitigating AMR on graft survival may be greater, with considerable benefits on improving human morbidity and mortality and opens the door to precision immunosuppression and extended tx survival.
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DOI：
10.1111/ajt.12589
发表时间：
2014-02
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Djamali A;Kaufman DB;Ellis TM;Zhong W;Matas A;Samaniego M
通讯作者：
Samaniego M
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Lonsdale, John;Thomas, Jeffrey;Salvatore, Mike;Phillips, Rebecca;Lo, Edmund;Shad, Saboor;Hasz, Richard;Walters, Gary;Garcia, Fernando;Young, Nancy;Foster, Barbara;Moser, Mike;Karasik, Ellen;Gillard, Bryan;Ramsey, Kimberley;Sullivan, Susan;Bridge, Jason;Magazine, Harold;Syron, John;Fleming, Johnelle;Siminoff, Laura;Traino, Heather;Mosavel, Maghboeba;Barker, Laura;Jewell, Scott;Rohrer, Dan;Maxim, Dan;Filkins, Dana;Harbach, Philip;Cortadillo, Eddie;Berghuis, Bree;Turner, Lisa;Hudson, Eric;Feenstra, Kristin;Sobin, Leslie;Robb, James;Branton, Phillip;Korzeniewski, Greg;Shive, Charles;Tabor, David;Qi, Liqun;Groch, Kevin;Nampally, Sreenath;Buia, Steve;Zimmerman, Angela;Smith, Anna;Burges, Robin;Robinson, Karna;Valentino, Kim;Bradbury, Deborah;Cosentino, Mark;Diaz-Mayoral, Norma;Kennedy, Mary;Engel, Theresa;Williams, Penelope;Erickson, Kenyon;Ardlie, Kristin;Winckler, Wendy;Getz, Gad;DeLuca, David;MacArthur, Daniel;Kellis, Manolis;Thomson, Alexander;Young, Taylor;Gelfand, Ellen;Donovan, Molly;Meng, Yan;Grant, George;Mash, Deborah;Marcus, Yvonne;Basile, Margaret;Liu, Jun;Zhu, Jun;Tu, Zhidong;Cox, Nancy J.;Nicolae, Dan L.;Gamazon, Eric R.;Im, Hae Kyung;Konkashbaev, Anuar;Pritchard, Jonathan;Stevens, Matthew;Flutre, Timothee;Wen, Xiaoquan;Dermitzakis, Emmanouil T.;Lappalainen, Tuuli;Guigo, Roderic;Monlong, Jean;Sammeth, Michael;Koller, Daphne;Battle, Alexis;Mostafavi, Sara;McCarthy, Mark;Rivas, Manual;Maller, Julian;Rusyn, Ivan;Nobel, Andrew;Wright, Fred;Shabalin, Andrey;Feolo, Mike;Sharopova, Nataliya;Sturcke, Anne;Paschal, Justin;Anderson, James M.;Wilder, Elizabeth L.;Derr, Leslie K.;Green, Eric D.;Struewing, Jeffery P.;Temple, Gary;Volpi, Simona;Boyer, Joy T.;Thomson, Elizabeth J.;Guyer, Mark S.;Cathy Ng;Abdallah, Assya;Colantuoni, Deborah;Insel, Thomas R.;Koester, Susan E.;Little, A. Roger;Bender, Patrick K.;Lehner, Thomas;Yao, Yin;Compton, Carolyn C.;Vaught, Jimmie B.;Sawyer, Sherilyn;Lockhart, Nicole C.;Demchok, Joanne;Moore, Helen F.
通讯作者：
Moore, Helen F.
DOI：
10.1073/pnas.0907939106
发表时间：
2009-09-29
影响因子：
11.1
作者：
da Cunha, J. P. C.;Galante, P. A. F.;de Souza, S. J.
通讯作者：
de Souza, S. J.