Identification and Development of Genetic Polymorphisms as Biomarkers of Graft ve

作为移植物生物标志物的遗传多态性的鉴定和开发

基本信息

批准号：
7509654
负责人：
Mukta Arora
金额：
$ 18.88万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7509654
关键词：
Accounting Acute Acute Graft Versus Host Disease Affect Age Algorithms Alleles Allogenic Allografting Amino Acids Biological Biological Factors Biological Markers Blood Candidate Disease Gene Cell Transplants Cells Cessation of life Clinical Cytokine Gene DNA Library Data Data Set Detection Development Disease Disease Pathway Future Genes Genetic Genetic Polymorphism Genetic Variation Goals Graph Hematopoietic Histocompatibility Immune Immune System Diseases Immune response Immunosuppressive Agents Incidence Inflammatory Lead Learning Literature Machine Learning Marrow Metabolism Methods Mining Minor Histocompatibility Antigens Morbidity - disease rate Numbers Outcome Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Population Heterogeneity Population Study Procedures Prophylactic treatment Public Health Publishing Range Rare Diseases Regression Analysis Regulator Genes Relapse Reporting Resources Risk Sampling Screening procedure Severities Standards of Weights and Measures Supportive care Techniques Technology Testing Therapeutic Agents Therapeutic Intervention Tissues Transplant Recipients Transplantation Validation Variant base chronic graft versus host disease clinical phenotype clinically relevant cohort design drug metabolism follow-up genetic variant genome wide association study graft vs host disease improved innovation mortality novel novel therapeutics prevent receptor tool validation studies

项目摘要

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplant continues to be associated with a high morbidity and mortality. Fifteen to 50% of patients die from complications related to the procedure. Graft-versus-host disease (GVHD) affects 20-80% of transplant recipients and is the major cause of post transplant non-relapse mortality. While some clinical parameters (e.g. age, donor: recipient histocompatibility) can predict GVHD, no biological factors have been identified that reliably predict the incidence and severity of GVHD and its associated mortality, as well as allow an understanding of the underlying pathogenesis of the disease, which, in turn could inform innovative treatment approaches. Hence, there exists a critical need to identify reliable biomarkers for the disease. We hypothesize that polymorphisms in genes regulating biological pathways of GVHD are associated with GVHD and transplant related mortality (TRM). We propose a candidate gene approach to analyze, in 838 subjects (donors and recipients), the relationship of 427 genetic polymorphisms which may modulate the immune response, inflammatory amplification and the metabolism of therapeutic agents with the incidence and course of GVHD and transplant related mortality. We will use conventional multiple variable regression analysis to identify relevant polymorphisms and will test novel machine based learning and graph based algorithms to identify gene patterns or interactions not recognizable with usual statistical techniques. Reliable genetic biomarkers would permit identification of high risk patients who need more effective prophylaxis or preemptive screening or therapeutic interventions to limit the severity of their graft versus host disease and ultimately to improve survival. Validation of our findings in a subsequent multicenter cohort could provide important data useful to inform the management of allograft patients and improve their outcomes. PUBLIC HEALTH RELEVANCE Graft-versus-host disease is a devastating disease that affects 20-70% of blood and marrow transplant (BMT) recipients. The disease is caused by an immune attack by donor cells on patient tissue. Some genetic factors, including polymorphisms (changes in amino acids in genes that alter their function) may predict patients at high risk of these complications. We aim to identify patients at high risk of complications and death, and subsequently modify their treatment, using the information we learn from our genetic studies, to alter their course. Our long term goal is to improve survival in these patients by determining groups at high risk towards whom intensive therapy should be targeted.

描述（由申请人提供）：同种异体造血细胞移植继续与高发病率和死亡率有关。 15％至50％的患者死于与该手术有关的并发症。移植物与宿主病（GVHD）影响20-80％的移植受者，是移植后非释放死亡率的主要原因。尽管某些临床参数（例如年龄，捐助者：受体组织相容性）可以预测GVHD，但尚未确定生物学因素可以可靠地预测GVHD及其相关死亡率的发病率和严重程度，并且允许对疾病的潜在病原体的理解，这反过来又可以使您的创新治疗能够接近创新的治疗方法。因此，存在确定可靠的生物标志物的迫切需要。我们假设调节GVHD生物学途径的基因中的多态性与GVHD和移植相关死亡率（TRM）有关。我们提出了一种候选基因方法，以分析838名受试者（捐助者和接受者），427种遗传多态性的关系可能调节免疫反应，炎症扩增以及治疗药物的代谢与GVHD的发生率和GVHD和相关死亡率的代谢。我们将使用常规的多变量回归分析来识别相关的多态性，并将测试基于机器的新型学习和基于图形的算法，以识别与通常的统计技术无法识别的基因模式或相互作用。可靠的遗传生物标志物将允许确定需要更有效的预防或先发制人筛查或治疗干预措施的高风险患者，以限制其移植物与宿主疾病的严重性，并最终提高生存率。在随后的多中心队列中对我们的发现的验证可能会提供重要数据，可用于告知同种异体患者的管理并改善其结果。公共卫生相关性移植物与宿主病是一种毁灭性疾病，影响20-70％的血液和骨髓移植（BMT）受体。该疾病是由供体细胞对患者组织的免疫发作引起的。某些遗传因素，包括多态性（基因中改变其功能的氨基酸的变化）可能会预测患者有这些并发症的高风险。我们的目的是使用我们从遗传研究中学习的信息来改变患者的高风险，并随后修改他们的治疗，以改变他们的过程。我们的长期目标是通过确定应针对强化治疗的高风险组来提高这些患者的生存。