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

多种族高通量研究，以确定血液和骨髓移植后死亡率的新非 HLA 遗传因素

• 批准号: 10456152
• 负责人: Alyssa Ione Clay-Gilmour
• 金额: $ 46.36万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456152
• 关键词: 10q21; 14q32; Affect; African American population; Allogenic; American; Antigens; Asian population; Bayesian Method; Binding; Biological; Biological Assay; Blood; Bone Marrow Transplantation; Clinical; Code; Collaborations; Data; Disease; Donor person; Ethnic Origin; Etiology; European; Funding; Genes; Genetic; Genetic study; Genomics; Genotype; Goals; Hematologic Neoplasms; Hematological Disease; Hispanic; Hispanic Populations; Immune response; Investments; Life; Linkage Disequilibrium; Machine Learning; Major Histocompatibility Complex; Methods; Minority; Minority Groups; Names; Pathway Analysis; Pathway interactions; Patients; Peptides; Play; Population; Population Heterogeneity; Predisposition; Race; Research; Resources; Risk; Role; Sampling; Signal Transduction; Surveys; Technology; Testing; Training; Translating; Transplant Recipients; Transplantation; United States National Institutes of Health; Validation; Variant; clinical practice; cohort; design; disorder risk; exome; exome sequencing; gene network; genetic variant; genome wide association study; genome-wide; improved; in silico; mortality; mortality risk; multi-ethnic; mutant; next generation sequencing; novel; polygenic risk score; prognostic model; rare variant; study population; survival disparity; survivorship; tool; transcriptome; vaccine response

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.

项目摘要 血液和骨髓移植(BMT)是许多危及生命的血液病的有效治疗方法。生死存亡 尽管骨髓移植在过去20年里有了显著的改善，但仍有高达40%的患者死于 人类白细胞抗原相合的无关供者异基因骨髓移植一年后。这个项目将建立在我们之前的全基因组基础上 (GWAS)和外显子组范围的关联研究(ExWAS)，涉及约2900名患者，名为确定 易感性变异对骨髓移植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者疾病相关死亡风险的供者基因座 (DRM)和供受者基因不匹配显著增加了移植相关死亡的风险 (TRM)在欧洲裔美国人(EA)中。我们的Exwas发现了一种罕见的非同义编码变体，其中 供受者基因错配与TRM和其他新基因(例如TEX38、OR51D1和 NT5E)与总生存期、TRM和DRM相关。我们这项提议的目标有两个：深化我们的 了解非人类白细胞抗原基因对骨髓移植死亡率的影响，并建立临床-基因组预后 将这种理解转化为临床实践的模型。第一个目标将在两个方向上实现。1) 我们将使用全外显子组测序(WES)和Meta-DNA技术系统地研究罕见和常见的变异体。 EAS和未充分研究的不同人群中的GWAS，以努力弥合骨髓移植存活差异 在东亚人、非裔美国人、亚裔和西班牙裔之间。我们之前在EAS的经验证明了 罕见的编码变异在骨髓移植死亡率中所起的作用，然而，只有2%的罕见变异位于外显子阵列中。 因此，我们将使用WES来分析5598对多种族供受者对中的所有外显子变异。作为 我们确定的变异/基因是因果关系的直接候选者，将执行功能验证以 调查这类关系。同时，我们将进行迄今为止最大规模的骨髓移植死亡率的Meta-Gwas评估。 通过我们的合作，我们已经收集了在美国可用的所有BMT Gwas数据(8576个捐赠者-接受者 包括1,978对少数民族对)。2)我们将询问WES和GWAS的数据，以进一步揭示生物 导致骨髓移植死亡的网络。为了实现第二个目标，我们将利用我们独特而强大的 GWAS资源用于开发预测患者个性化死亡风险的预后模型。这是第一次 利用下一代测序技术分析非人类白细胞抗原编码变异对人类免疫缺陷的贡献 骨髓移植后死亡率。关于8,576对捐赠者-受赠者的Gwas数据，其中5,598对也有WES数据，将 使这项研究成为有史以来最大的遗传学研究，并提供一个真正的机会来理解遗传学 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 在常规临床实践中帮助降低骨髓移植死亡率并加强供受者配型。重要的是， 该项目生成的数据将被公开共享，作为进一步研究改进的资源 在BMT后生存，并增加对该项目的公共投资。