Whole Genome Association Analysis of Hematopoietic Cell Transplant Outcome

造血细胞移植结果的全基因组关联分析

• 批准号: 7226822
• 负责人: John Andrew Hansen
• 金额: $ 173.92万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226822
• 关键词: biotechnology; cell bank /registry; cell transplantation; clinical research; gene interaction; genetic screening; genetic susceptibility; genome; graft versus host disease; hematopoietic tissue transplantation; hepatotoxin; human data; human genetic material tag; human tissue; immune tolerance /unresponsiveness; immunogenetics; infection; linkage disequilibriums; molecular biology information system; pulmonary fibrosis /granuloma; quantitative trait loci; renal toxin; single nucleotide polymorphism; tissue donors

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.

描述（由申请人提供）：先前的研究已经证明，同种异体造血细胞移植（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着移植后并发症和综合征风险的基因型，包括急性和慢性 GHVD、肝肾毒性、肺部综合征、细菌、病毒和真菌感染，以及影响发育的遗传因素的免疫耐受性。本研究提出的 HCT 人群代表了相对较多的患者，他们在结构化环境中接受了严格的方案控制治疗，并详细监测和记录了关键数据。该数据集富含临床相关表型。本研究的主题并发症会影响发病率和死亡率，多年来已被证明它们代表了与 HCT 接受者以外的人群相关的疾病信息模型系统。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。第一个目标是对由 1,000 个 HCT 病例（患者-捐赠者对，2,000 个样本）组成的队列进行单核苷酸多态性 (SNP) 的全基因组扫描，这些病例是从更大的移植患者群体中随机选择的，这些患者按照统一的方案在移植中心进行移植。单中心。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）。第二个具体目标是应用关键的生物信息学工具和创新的统计方法来分析全基因组数据和 HCT 结果，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。我们提出了一种三阶段方法来定义遗传多态性和识别功能变异。首先，将定义移植患者和捐赠者的基因组变异。第二阶段将探索与复杂表型的遗传关联（SNP/单倍型），分析基因关联以及基因与基因之间的相互作用与事件发生时间表型和数量性状。第三阶段将探索接受者和捐赠者之间的基因组间相互作用。