Whole Genome Association Analysis of Hematopoietic Cell Transplant Outcome

描述（由申请人提供）： 以往的研究表明，异基因造血细胞移植（HCT）的结果可能会受到遗传变异的影响。本研究项目中提出的研究目标是通过全基因组关联分析来表征造成这些差异的供体和受体遗传成分。具体目标是确定影响临床显著的移植后并发症和综合征的风险的基因型，包括急性和慢性GHVD，肝脏和肾脏毒性，肺部综合征，细菌，病毒和真菌感染，以及影响免疫耐受性发展的遗传因素。本研究拟定的HCT人群代表了相对较多的患者，这些患者在结构化环境中接受了密集的方案对照治疗，并详细监测和记录了关键数据。该数据集具有丰富的临床相关表型。作为本研究主题的并发症影响发病率和死亡率，多年来已证明它们代表了与HCT接受者以外的人群相关的疾病的信息模型系统。这项HCT研究的一个独特之处是有机会分析患者和供体的基因型，以及这种相互作用对疾病表型和移植结果的影响。第一个目标是在由1，000例HCT病例（患者-供体对，2，000份样本）组成的队列中进行单核苷酸多态性（SNP）的全基因组扫描，这些病例是根据单一中心的统一方案从更大的移植患者人群中随机选择的。主要表型定义的移植结果是急性GVHD、慢性GVHD、HCT相关气流阻塞（AFO）和免疫耐受。次要表型包括特发性肺炎综合征、急性肝病、肾功能受损和感染性疾病（细菌、病毒和真菌）。第二个具体目标是将关键的生物信息学工具和创新的统计方法应用于全基因组数据和HCT结果的分析，并确定不同基因之间以及供体和受体遗传变异之间的相互作用。我们提出了一个3阶段的方法来定义遗传多态性和识别功能变异。首先，将在移植患者和供体中定义基因组变异。第二阶段将探索与复杂表型的遗传关联（SNP/单倍型），分析基因和基因-基因相互作用与事件发生时间表型和数量性状的关联。第三阶段将探索受体和供体之间的基因组-基因组相互作用。

DESCRIPTION (provided by applicant): Previous studies have demonstrated that allogeneic hematopoietic cell transplant (HCT) outcome may be affected by genetic variation. The goals of the studies proposed in this research project are to characterize by genome-wide association analysis the donor and recipient genetic components responsible for these differences. Specific objectives are to identify genotypes that affect the risks of the clinically significant post-transplant complications and syndromes including acute and chronic GHVD, liver and renal toxicity, pulmonary syndromes, bacterial, viral and fungal infections, and also the genetic factors that affect the development of immunological tolerance. The HCT population proposed for this study represents a relatively large number of patients who have undergone intense protocol-controlled therapy in a structured environment with detailed monitoring and recording of critical data. The dataset is rich in clinically relevant phenotypes. The complications that are the subject of this study affect morbidity and mortality, and they have over the years proven to represent informative model systems of disease relevant to populations other than HCT recipients. A unique feature of this HCT study is the opportunity to analyze both patient and donor genotype, and the effect this interaction has on disease phenotype and transplant outcome. The first aim is to perform a whole genome scan of single nucleotide polymorphisms (SNP) in a cohort consisting of 1,000 HCT cases (patient-donor pairs, 2,000 samples), randomly selected from a larger population of patients transplanted according to uniform protocols at a single Center. The primary phenotype-defined transplant outcomes are acute GVHD, chronic GVHD, HCT-related airflow obstruction (AFO) and immunological tolerance. Secondary phenotypes include idiopathic pneumonia syndrome, acute liver disease, impaired renal function and infections diseases (bacterial, viral and fungal). The second specific aim is to apply critical bioinformatics tools and innovative statistical methods to the analysis of whole genome data and HCT outcomes, and determine interactions between different genes and between donor and recipient genetic variants. We propose a 3-stage approach to defining genetic polymorphism and identifying functional variants. First, genomic variation will be defined in transplant patients and donors. The second stage will explore genetic associations (SNPs/Haplotypes) with complex phenotypes, analyzing associations of genes and gene-gene interactions with time-to-event phenotypes and quantitative traits. The third stage will explore genome-genome interactions between recipient and donor.