Multi-ethnic high-throughput study to identify novel non-HLA genetic contributors to mortality after blood and marrow transplantation

项目摘要 血液和骨髓移植（BMT）是治疗许多危及生命的血液病的有效方法。生存 在过去的二十年里，BMT有了显着的改善，然而，高达40%的患者仍然在 在HLA匹配的非亲缘异基因骨髓移植后一年。该项目将建立在我们先前的全基因组 GWAS和Exome-wide association studies（ExWAS）涉及约2，900名患者，名为Determining the 易感性变异对BMT后一年死亡率的影响（DISCOVeRY-BMT） 我们的GWAS确定了几个显著增加受体疾病相关死亡风险的供体基因座 (DRM)供体-受体基因型错配显著增加了移植相关死亡的风险 (TRM)欧洲裔美国人（EAs）。我们的ExWAS发现了一种罕见的非同义编码变体， 供体-受体基因型错配与TRM和其他新基因（如TEX 38，OR 51 D1， NT 5E）与总生存率、TRM和DRM相关。我们提出这一建议的目的有两个：深化我们的 了解BMT死亡率的非HLA遗传因素，并建立临床基因组预后 将这种理解转化为临床实践。第一个目标将在两个方向实现。第一章 我们将使用全外显子组测序（WES）和Meta分析系统地调查罕见和常见的变异。 在EA以及研究不足的不同人群中进行GWAS，以缩小BMT生存率的差异 非裔美国人亚裔和西班牙裔之间的差异我们之前在EA中的ExWAS证明了 然而，罕见编码变异在BMT死亡率中所起的作用，只有2%的罕见变异在外显子组阵列中。 因此，我们将使用WES来分析5，598个多种族供体-受体对中的所有外显子变体。为 我们识别的变异/基因是因果关系的直接候选者，将进行功能验证， 调查这种关系。同时，我们将进行迄今为止最大的BMT死亡率荟萃GWAS。 通过我们的合作，我们收集了美国所有可用的BMT GWAS数据（8，576名供体-受体 包括1，978对少数民族）。2)我们将询问WES和GWAS数据，以进一步揭示生物学特征。 导致BMT死亡的网络。为了实现第二个目标，我们将利用我们独特而强大的 GWAS资源开发预后模型以预测患者的个性化死亡风险。这是第一 研究使用下一代测序技术分析非HLA编码变体对 BMT后死亡率。GWAS对8，576个捐赠者-接受者对的数据，其中5，598对也有WES数据，将 使之成为有史以来规模最大的遗传学研究，并提供一个真实的机会来了解遗传学。 不同人群的骨髓移植死亡率。我们开发的预测模型将提供一个有价值的工具， 有助于降低BMT死亡率，并在常规临床实践中增强供体-受体匹配。重要的是 该项目产生的数据将公开共享，作为进一步研究的资源，以改善 BMT后的生存，并增加该项目的公共投资。

Project Summary Blood and marrow transplant (BMT) is an effective cure for many life-threatening hematologic diseases. Survival after BMT has improved dramatically over the past two decades, however up to 40% of patients still die within one year after HLA-matched unrelated donor allogeneic BMT. This project will build upon our prior genome-wide (GWAS) and exome-wide association studies (ExWAS) involving ~2,900 patients named Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT (DISCOVeRY-BMT). Our GWAS identified several donor loci that significantly increased recipient’s risk of disease-related mortality (DRM) and donor-recipient genotype mismatches significantly increased risk of transplant-related mortality (TRM) in European Americans (EAs). Our ExWAS discovered a rare nonsynonymous coding variant, where a donor-recipient genotype mismatch correlated with TRM and additional novel genes (e.g. TEX38, OR51D1, and NT5E) correlated with overall survival, TRM and DRM. Our goal for this proposal is two-fold: to deepen our understanding of non-HLA genetic contributors to BMT mortality, and to build the clinical-genomic prognostic models to translate such understanding into clinical practice. The first goal will be fulfilled in two directions. 1) We will systematically survey both rare and common variants using whole-exome sequencing (WES) and meta- GWAS in EAs as well as under-studied diverse populations in an effort to bridge the BMT survival disparity between EAs, African Americans, Asians and Hispanics. Our prior ExWAS in EAs demonstrated the important roles played by rare coding variants in BMT mortality, however, only 2% of rare variants are in the exome array. Therefore, we will use WES to assay all exonic variants in 5,598 multi-ethnic donor-recipient pairs. As the variants/genes we identify are direct candidates for causality, functional validation will be performed to investigate such relationships. In parallel, we will perform the largest meta-GWAS of BMT mortality to date. Through our collaborations, we have assembled all BMT GWAS data available in the US (8,576 donor-recipient pairs including 1,978 minority pairs). 2) We will interrogate WES and GWAS data to further reveal the biological networks contributing to BMT mortality. To meet the second goal, we will leverage our unique and powerful GWAS resource to develop prognostic models to predict patients’ personalized mortality risk. This is the first study to use next-generation sequencing technology to analyze the contribution of non-HLA coding variants on post-BMT mortality. GWAS data on 8,576 donor-recipient pairs, of which 5,598 pairs also have WES data, will make this the largest genetic study ever undertaken, and provide a real opportunity to understand the genetics of BMT mortality across diverse populations. The prognostic models we develop will provide a valuable tool to help reduce BMT mortality and enhance donor-recipient matching in routine clinical practice. Importantly, the data generated by this project will be shared publicly to serve as a resource for additional research to improve survivorship after BMT and enhance the public investment in this project.