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

描述（由申请人提供）：本R 01提案的目标是识别影响异基因造血细胞移植（HCT）并发症和风险的遗传变异。经验证的发现将提供必要的信息，以大大改善风险评估，咨询，治疗计划，并指导未来的机制研究的基因和途径，控制复杂的HCT后表型，从而提供洞察力和新的靶向治疗的理由。该提案的近期目标是（1）扩大现有发现队列，以显著提高检测与HCT结果相关的其他遗传变异的能力;（2）使用GWAS-HCT数据库进行计算机模拟候选基因研究，以复制先前发表的研究结果;和（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，并使用该测量来测试与GVHD、复发和死亡率的关联，和ii）鉴定编码次要组织相容性抗原的非MHC基因座，所述次要组织相容性抗原用作GVHD和移植物抗白血病（GVL）效应的靶。目前的研究工作将代表我们在R 01 HL 087690（09/25/2006-07/31/2009）的支持下于2006年启动的GWAS-HCT的扩展，该研究使用Affytek 5.0基因芯片对1，553例HCT病例（> 3，000例患者和供体样本）进行了基因组扫描。迄今为止的分析显示，与赋予2倍或更高风险的基因座相关。然而，低于该阈值的效应可能识别出更多新的致病途径，需要更大的统计功效。第一个具体目标是扩大GWAS-HCT项目，以包括1988年至2009年在我们中心移植的所有患者，使移植总数达到约5，000例（约10，000例患者和供体）。将样本量增加>300%将提高在低至1.5的几率范围内检测与HCT结果相关的遗传变异的功效，并提供机会以包括在该患者群体中发生的频率低至10- 15%的额外高优先级但低发生率的临床表型。分析的HCT结局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（阿基）、革兰氏阴性菌血症、侵袭性真菌病、CMV感染和疾病、疾病复发和移植相关死亡率。我们还将采用一种创新的方法来分析供体与供体之间的遗传差异，以确定导致GVHD和移植物抗白血病（GVL）效应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提供，并将为利用HCT遗传学更广泛地改善HCT安全性和有效性提供新的机会。 公共卫生相关性：我们建议进行造血细胞移植（HCT）结果的全基因组关联研究（GWAS），以确定为什么总体结果和并发症因患者而异。这项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、机会性感染和总生存期的风险和严重程度相关的遗传多态性。该研究将包括5，000例移植病例（10，000名患者和供体）。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志物。发现的基因和途径将为这些并发症的疾病过程提供机制性见解，并为开发预防和控制这些并发症的新型靶向治疗提供理论基础。

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.