Whole Genome Association Analysis of Hematopoietic Cell Transplant (HCT) Outcome

造血细胞移植 (HCT) 结果的全基因组关联分析

• 批准号: 8022984
• 负责人: John Andrew Hansen
• 金额: $ 244.5万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022984
• 关键词: Acute; Acute Graft Versus Host Disease; Acute Renal Failure with Renal Papillary Necrosis; Affect; Allogenic; Bacteremia; Biological Models; Bronchiolitis Obliterans; Candidate Disease Gene; Cell Transplants; Clinical; Clinical Research; Collaborations; Communities; Complex; Computer Simulation; Counseling; Cytomegalovirus; DNA; Data; Data Set; Databases; Development; Disease; Environment; Frequencies; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome Scan; Genomics; Genotype; Goals; Hematologic Neoplasms; Hematopoietic; Human; Immune; Incidence; Infection; Lead; Link; Measures; Mediating; Minor; Minor Histocompatibility Antigens; Monitor; Morbidity - disease rate; Obstruction; Odds Ratio; Opportunistic Infections; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Population; Population Study; Process; Protocols documentation; Publications; Publishing; Recurrent disease; Relapse; Research; Resource Sharing; Resources; Risk; Risk Assessment; Safety; Sample Size; Sampling; Scanning; Severities; Structure; Syndrome; Testing; Toxic effect; Transplant Recipients; Transplant-Related Disorder; Transplantation; United States National Institutes of Health; chronic graft versus host disease; clinical phenotype; clinically relevant; clinically significant; cohort; database of Genotypes and Phenotypes; design; genetic variant; genome wide association study; genome-wide; graft vs host disease; graft vs leukemia effect; histocompatibility gene; improved; innovation; insight; mortality; new therapeutic target; novel; patient population; prevent; response; transplant database; treatment planning

DESCRIPTION (provided by applicant): The goal of this R01 proposal is to identify genetic variants that affect complications and risks of allogeneic hematopoietic cell transplant (HCT). Validated discoveries will provide the information necessary to greatly improve risk assessment, counseling, treatment planning and to direct future mechanistic studies of the genes and pathways that control the complex post-HCT phenotypes thereby providing insight and rationale for new targeted therapies. The immediate objectives of this proposal are (1) to enlarge the existing discovery cohort to significantly increase power for detecting additional genetic variants associated with HCT outcomes; (2) perform an in silico candidate gene study using the GWAS-HCT database to replicate results of previously published studies; and (3) develop an innovative approach to i) measuring genome-wide genetic disparity between donor and recipient, and using this measure to test for association with GVHD, relapse and mortality, and ii) identifying non-MHC loci encoding minor histocompatibility antigens that serve as the targets for GVHD and the graft-vs-leukemia (GVL) effect. The current research effort will represent an extension of a GWAS-HCT we initiated in 2006 with the support of R01 HL087690 (09/25/2006-07/31/2009) which generated genome scans for 1,553 HCT cases (>3,000 patient and donor samples) using the Affymetrix 5.0 GeneChip. Analyses thus far have revealed associations with loci conferring risks of 2-fold or greater. However, effects below this threshold, which may identify many more novel pathogenic pathways, require greater statistical power. The first specific aim is to expand the GWAS-HCT project to include all patients transplanted at our Center from 1988 through 2009, bringing the total number to ~5,000 transplants (~10,000 patients and donors). Increasing the sample size by >300% will improve power for detecting genetic variants associated with HCT outcomes across a range of odds as low as 1.5, and provide opportunity for including additional high priority but low incidence clinical phenotypes that occur in this patient population with a frequencies as low as 10-15%. The HCT outcomes phenotypes analyzed will include acute and chronic GVHD, immunological tolerance, airflow obstruction (AFO disease/bronchiolitis obliterans syndrome (BOS), acute kidney injury (AKI), Gram negative bacteremia, invasive fungal disease, CMV infection and disease, disease relapse and transplant-related mortality. We will also apply an innovative approach to the analysis of recipient-donor genetic disparity to identify the minor histocompatibility genes responsible for GVHD and the graft-vs-leukemia (GVL) effect. This comprehensive genetic and rich phenotype data will be available through dbGaP, and will provide a novel opportunity for leveraging HCT genetics for the broader improvement of HCT safety and efficacy. PUBLIC HEALTH RELEVANCE: We propose performing a genome-wide association study (GWAS) of hematopoietic cell transplant (HCT) outcomes to determine why overall results and complications vary from patient to patient. The proposed study is designed to indentify genetics polymorphisms associated with the risk and severity of acute and chronic graft-versus-host disease (GVHD), organ toxicity, opportunistic infection and overall survival. The study will include 5,000 transplant cases (10,000 patients and donors). Genetic variants associated with HCT outcome will be validated as markers for assessing risk prior to transplant, counseling, treatment planning. The genes and pathways discovered will provide mechanistic insight into the disease processes responsible for these complications and the rationale for developing novel targeted therapies for preventing and controlling these complications.

描述（由申请人提供）：该 R01 提案的目标是识别影响同种异体造血细胞移植 (HCT) 并发症和风险的遗传变异。经过验证的发现将提供必要的信息，以极大地改善风险评估、咨询、治疗计划，并指导未来对控制复杂的 HCT 后表型的基因和途径的机制研究，从而为新的靶向治疗提供见解和理由。该提案的直接目标是（1）扩大现有的发现队列，以显着提高检测与 HCT 结果相关的其他遗传变异的能力； (2) 使用 GWAS-HCT 数据库进行计算机候选基因研究，以复制先前发表的研究结果； (3) 开发一种创新方法，i) 测量供体和受体之间的全基因组遗传差异，并使用这种测量方法来测试与 GVHD、复发和死亡率的关联，以及 ii) 识别编码次要组织相容性抗原的非 MHC 位点，作为 GVHD 和移植物抗白血病 (GVL) 效应的靶标。目前的研究工作将是我们于 2006 年在 R01 HL087690 (09/25/2006-07/31/2009) 支持下启动的 GWAS-HCT 的延伸，该项目为 1,553 个 HCT 病例（> 3,000 名患者和捐赠者）生成了基因组扫描样品）使用 Affymetrix 5.0 GeneChip。迄今为止的分析揭示了与赋予两倍或更高风险的基因座的关联。然而，低于该阈值的效应可能会识别更多新的致病途径，需要更大的统计能力。第一个具体目标是扩大 GWAS-HCT 项目，将 1988 年至 2009 年期间在我们中心接受移植的所有患者纳入其中，使移植总数达到约 5,000 例（约 10,000 名患者和捐献者）。将样本量增加 > 300% 将提高检测与 HCT 结果相关的遗传变异的能力，其赔率范围低至 1.5，并提供机会纳入该患者群体中发生的其他高优先级但低发生率的临床表型，这些临床表型具有以下特点：频率低至 10-15%。分析的 HCT 结果表型将包括急性和慢性 GVHD、免疫耐受、气流阻塞（AFO 疾病/闭塞性细支气管炎综合征 (BOS)、急性肾损伤 (AKI)、革兰氏阴性菌血症、侵袭性真菌病、CMV 感染和疾病、疾病复发）我们还将应用创新方法来分析受者-供者遗传差异，以确定导致 GVHD 和移植物相关性的次要组织相容性基因。这种全面的遗传和丰富的表型数据将通过 dbGaP 获得，并将为利用 HCT 遗传学来更广泛地提高 HCT 安全性和有效性提供新的机会。 公共健康相关性：我们建议对造血细胞移植（HCT）结果进行全基因组关联研究（GWAS），以确定为什么总体结果和并发症因患者而异。拟议的研究旨在确定与急性和慢性移植物抗宿主病（GVHD）、器官毒性、机会性感染和总体生存的风险和严重程度相关的遗传多态性。该研究将包括 5,000 个移植病例（10,000 名患者和捐赠者）。与 HCT 结果相关的遗传变异将被验证为移植前评估风险、咨询、治疗计划的标记。发现的基因和途径将为了解导致这些并发症的疾病过程提供机制上的见解，并为开发预防和控制这些并发症的新型靶向疗法提供依据。