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: 8212026
• 负责人: John Andrew Hansen
• 金额: $ 241.71万
• 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/8212026
• 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; Gene Chips; 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; public health relevance; 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提案的目的是确定影响并发症和同种异体造血细胞移植（HCT）风险的遗传变异。经过验证的发现将提供大大改善风险评估，咨询，治疗计划的必要信息，并指导控制复杂的HCT表型基因和途径的未来机械研究，从而为新的靶向疗法提供见识和理由。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功率； （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的结果； （3）开发一种创新的方法i）测量供体和受体之间的全基因组遗传差异，并使用此措施来测试与GVHD，复发和死亡率相关的，以及ii）识别编码非MHC基因座，编码次要的组织能力抗原，以作为GRAFT-VHD和GRAFT-VS-VS-LEUKEMIAD（GVL）效应（GVL）（GVL）（GVL）（GVL）（GVL）。当前的研究工作将代表我们在2006年启动的GWAS-HCT的扩展，并在R01 HL087690（09/25/2006-07/31/2009）的支持下，使用Affymetrix 5.0 Genechithephephip.5.0 Genechithaped生成了1,553 HCT病例（> 3,000名患者和供体样品）的基因组扫描。到目前为止，分析揭示了与基因座赋予2倍或更高风险的关联。但是，在此阈值以下的效果（可能识别出更多新颖的致病途径）需要更大的统计能力。第一个具体目的是扩大GWAS-HCT项目，以包括1988年至2009年在我们中心移植的所有患者，将总数达到约5,000次移植（约10,000名患者和捐助者）。将样本量增加> 300％将提高检测与HCT结果相关的遗传变异的功率，并在低至1.5的范围内提高与HCT结果相关的遗传变异，并为在该频率低至10-15％的频率的患者人群中提供了额外的高优先级但较低的发病率临床表型。分析的HCT结果表型将包括急性和慢性GVHD，免疫学耐受性，气流障碍（AFO病/支气管炎/支气管炎闭塞综合征（BOS），急性肾脏损伤（AKI），革兰州阴性细菌，侵入性侵入性疾病，CMV感染，疾病疾病和疾病的疾病相关性以及跨性别的方法，以及跨性别的方法。接受者遗传差异确定了负责GVHD的较小组织相容性基因和Graft-VS-Leukemia（GVL）效应。 公共卫生相关性：我们建议对造血细胞移植（HCT）结局进行全基因组关联研究（GWAS），以确定为什么整体结果和并发症因患者而异。拟议的研究旨在抑制与急性和慢性移植物抗宿主病（GVHD），器官毒性，机会性感染和整体生存相关的遗传学多态性。该研究将包括5,000例移植病例（10,000例患者和捐助者）。与HCT结果相关的遗传变异将被验证为在移植，咨询，治疗计划之前评估风险的标记。发现的基因和途径将提供有关这些并发症的疾病过程的机理洞察力，以及开发新的有针对性疗法以防止和控制这些并发症的基本原理。