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: 10671064
• 负责人: Alyssa Ione Clay-Gilmour
• 金额: $ 50.31万
• 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/10671064
• 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.

项目概要 血液和骨髓移植（BMT）是许多危及生命的血液疾病的有效治疗方法。 尽管 BMT 在过去二十年中取得了显着改善，但仍有高达 40% 的患者在体内死亡 HLA 匹配的无关供体同种异体 BMT 一年后，该项目将建立在我们之前的全基因组范围内。 (GWAS) 和全外显子组关联研究 (ExWAS)，涉及约 2,900 名患者，名为“确定 易感性传播变异对 BMT 后一年死亡率的影响 (DISCOVeRY-BMT)。 我们的 GWAS 确定了几个显着增加受者疾病相关死亡风险的供体位点 (DRM) 和供体-受体基因型不匹配显着增加移植相关死亡的风险 (TRM) 在欧洲美国人 (EA) 中我们的 ExWAS 发现了一种罕见的非同义编码变体，其中 供体-受体基因型不匹配与 TRM 和其他新基因（例如 TEX38、OR51D1 和 NT5E）与总体生存率、TRM 和 DRM 相关。我们此提案的目标有两个：深化我们的研究。 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的模型将在两个方向上实现。 我们将使用全外显子组测序（WES）和元测序系统地调查罕见和常见的变异。 EA 中的 GWAS 以及未充分研究的不同人群，旨在缩小 BMT 生存差异 我们之前在 EA 中的 ExWAS 证明了这一点的重要性。 罕见编码变异在 BMT 死亡率中发挥着重要作用，但只有 2% 的罕见变异存在于外显子组阵列中。 因此，我们将使用 WES 检测 5,598 个多种族供体-受体对中的所有外显子变异。 我们确定的变异/基因是因果关系的直接候选者，将进行功能验证 与此同时，我们将开展迄今为止最大规模的 BMT 死亡率元 GWAS。 通过我们的合作，我们收集了美国可用的所有 BMT GWAS 数据（8,576 名捐赠者-接受者 2）我们将询问WES和GWAS数据以进一步揭示生物学 为了实现第二个目标，我们将利用我们独特而强大的网络。 GWAS 资源用于开发预后模型来预测患者的个性化死亡风险。 研究利用下一代测序技术来分析非 HLA 编码变异对 8,576 对供体-受者对的 BMT 后死亡率，其中 5,598 对也有 WES 数据。 使这是有史以来最大规模的基因研究，并提供了解遗传学的真正机会 我们将开发的预后模型将为不同人群的 BMT 死亡率提供有价值的工具。 有助于降低 BMT 死亡率并增强常规临床实践中的供体-受体匹配。 该项目生成的数据将公开共享，作为进一步研究的资源，以改进 BMT 后的生存并增加对该项目的公共投资。