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

描述(由申请人提供)：本R01提案的目标是确定影响异基因造血细胞移植(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，以极大地改进风险评估、咨询和治疗计划，并指导未来对控制HCT后复杂表型的基因和途径的机械性研究，从而为新的靶向治疗提供洞察力和理论基础。这项建议的近期目标是(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)利用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；以及(3)开发一种创新的方法，以i)测量供者和受者之间的全基因组遗传差异，并使用该方法来测试与GVHD、复发和死亡率的相关性，以及ii)识别编码微小组织相容抗原的非MHC基因座，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(09/25/2006-07/31/2009)的支持下于2006年启动的GWAS-HCT的扩展，该R01 HL087690使用Affymetrix 5.0基因芯片生成了1,553例HCT病例(&gt；3,000名患者和捐赠者样本)的基因组扫描。到目前为止，分析已经揭示了与2倍或更大风险的基因座的关联。然而，低于这一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年期间在我们中心移植的所有患者包括在内，使移植总数达到约5,000例(约10,000名患者和捐赠者)。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能力，并提供机会包括在频率低至10%-15%的患者群体中出现的其他高优先级但低发生率的临床表型。分析的HCT结局表型包括急性和慢性移植物抗宿主病、免疫耐受、气流阻塞(AFO病/细支气管炎闭塞综合征)、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供受者的遗传差异，以确定与移植物抗白血病(GVL)效应和移植物抗白血病(GVL)效应有关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遗传学更广泛地改善HCT的安全性和有效性提供一个新的机会。

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.