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

摘要 R01提案的目标是确定与并发症相关的单核苷酸多态(SNPs 异基因造血细胞移植(HCT)后。经过验证的发现将提供必要的信息，以大大 改进风险评估、咨询、治疗计划，并指导未来对基因和途径的机制研究 控制HCT后复杂的表型，从而为新的靶向治疗提供洞察力和理论基础。这个 这项建议的近期目标是(1)进行GWAS发现研究，以确定与 Hct发现和扩展数据集的复制GWA后的显著结果；(2)测试符合以下条件的SNP等位基因 受者不匹配，并且已知或被提议编码与GVHD相关的次要组织相容性抗原- HCT后的相关结果；以及(3)进行计算机候选基因研究以复制先前发表的结果 来自HCT文献和NHGRI Gwas目录的研究。9,118名患者和捐赠者的全基因组。小儿麻痹症 分析的结果表型包括急性和慢性移植物抗宿主病、急性肾损伤、免疫耐受、 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，无复发死亡率和 总体存活率。我们还将应用一种创新的方法来分析受者和捐赠者的遗传差异，以确定 与移植物抗白血病(GVL)效应和移植物抗白血病(GVL)相关的次要组织相容性基因。这一全面的遗传 而丰富的表型数据将通过DBGaP获得，并将为利用HCT遗传学 HCT安全性和有效性的更大范围的提高。

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.