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

描述（由申请人提供）：本R01申请的目的是确定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，以大大改善风险评估、咨询、治疗计划，并指导未来控制复杂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论依据。本提案的直接目标是：(1)扩大现有的发现队列，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)开发一种创新的方法，以i)测量供体和受体之间的全基因组遗传差异，并使用该方法检测与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，这些抗原可作为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在R01 HL087690（2006年9月25日- 2009年7月31日）的支持下于2006年启动的GWAS-HCT的延伸，该项目使用Affymetrix 5.0基因芯片对1553例HCT病例（bbb3000例患者和供体样本）进行了基因组扫描。迄今为止的分析已经揭示了与基因座相关的2倍或更高的风险。然而，低于这个阈值的效应可能会识别出许多新的致病途径，需要更大的统计能力。第一个具体目标是扩大GWAS-HCT项目，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例患者和捐赠者）。将样本量增加100 - 300%将提高检测与HCT结果相关的遗传变异的能力，其几率低至1.5，并提供机会包括在该患者群体中发生的频率低至10-15%的其他高优先级但低发病率的临床表型。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、巨细胞病毒感染和疾病、疾病复发和移植相关死亡率。我们还将应用一种创新的方法来分析受体-供体遗传差异，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。这些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遗传学更广泛地提高HCT的安全性和有效性提供新的机会。

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.