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

造血细胞移植 (HCT) 结果的全基因组关联分析

基本信息

批准号：
9389761
负责人：
John Andrew Hansen
金额：
$ 77.98万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9389761
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Affect Alleles Allogenic Bacteremia Candidate Disease Gene Catalogs Cell Transplants Clinical Clinical Data Clinical Investigator Clinical Research Collaborations Communities Complex Computer Simulation Counseling Cytomegalovirus Infections Data Data Set Development Disease Donor person Dysmyelopoietic Syndromes Environment Failure Foundations Fred Hutchinson Cancer Research Center Funding Future Gene Chips Genes Genetic Genetic Polymorphism Genetic Variation Genetic study Genome Genotype Goals Hematologic Neoplasms Hematopoietic Human Human Genetics Immune Tolerance Literature Methods Minor Minor Histocompatibility Antigens Monitor Morbidity - disease rate National Human Genome Research Institute Opportunistic Infections Organ Outcome Pathogenesis Pathway interactions Patients Phenotype Process Publishing Recurrent disease Relapse Reporting Research Personnel Resource Sharing Resources Risk Risk Assessment Role Safety Sampling Scientist Severities Single Nucleotide Polymorphism Structure Testing Toxic effect Transplant Recipients Transplantation United States National Institutes of Health Variant chronic graft versus host disease clinically relevant cohort cost database of Genotypes and Phenotypes design genetic variant genome wide association study genome-wide graft vs host disease graft vs leukemia effect histocompatibility gene improved innovation insight leukemia mortality new therapeutic target novel operation phenotypic data prevent response study population success treatment planning

项目摘要

Summary The goal of this R01 proposal is to identify single nucleotide polymorphisms (SNPs) that are associated with complications after 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 perform GWAS discovery studies to identify genetic variants associated with significant outcomes after HCT discovery and replication GWAS of the expanded data set; (2) to test SNP alleles that are mismatched in the recipient and are known or proposed to encode minor histocompatibility antigens associated with GVHD- related outcomes after HCT; and (3) perform an in silico candidate gene studies to replicate results of previously published studies from the HCT literature and the NHGRI GWAS Catalog. genome-wide for 9,118 patients and donors. The HCT outcomes phenotypes analyzed will include acute and chronic GVHD, acute kidney injury (AKI), immunologic tolerance, Gram negative bacteremia, invasive fungal disease, CMV infection and disease, disease relapse, nonrelapse mortality and overall survival. 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.

概括该R01建议的目的是识别与并发症相关的单核苷酸多态性（SNP）同种异体造血细胞移植（HCT）之后。经过验证的发现将提供必要的信息改善风险评估，咨询，治疗计划，并指导基因和途径的未来机械研究这样可以控制复杂的HCT表型，从而为新的靶向疗法提供了洞察力和理由。这该提案的直接目标是（1）进行GWAS发现研究以识别与 HCT发现和复制GWA的大量结果的大量结果；（2）测试SNP等位基因在接受者中匹配不匹配，并提议编码与GVHD-相关的小组织相容性抗原 HCT之后的相关结果；（3）进行计算机候选基因研究以复制先前发表的结果 HCT文献和NHGRI GWAS目录的研究。全基因组为9118名患者和供体提供。 HCT 分析的结果表型将包括急性和慢性GVHD，急性肾损伤（AKI），免疫耐受性，革兰氏阴性菌血症，侵入性真菌疾病，CMV感染和疾病，疾病复发，非逆转死亡率和总体生存。我们还将应用一种创新的方法来分析接受者遗传差异，以识别负责GVHD和GRAFT-VS-Leukemia（GVL）效应的较小组织相容性基因。这种全面的遗传丰富的表型数据将通过DBGAP获得，并将为利用HCT遗传学提供新的机会 HCT安全性和功效的更大改善。