Genetic Variation in Vitamin D Metabolism and BMT Outcomes

维生素 D 代谢和 BMT 结果的遗传变异

• 批准号: 7509511
• 负责人: Kimberly Z Robien
• 金额: $ 16.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509511
• 关键词: 25-hydroxyvitamin D; Acute; Adult; Adverse effects; Allogenic; Anabolism; Blood; Bone Marrow Transplantation; Breast; CYP3A4 gene; Calcium; Catabolism; Cell Cycle; Childhood; Colon; Communicable Diseases; DNA; Data; Databases; Dietary Intervention; Disease regression; Disease-Free Survival; Enzymes; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Genus Cola; Goals; Haplotypes; Health; Hematologic Neoplasms; Hodgkin Disease; Homeostasis; Hormones; Incidence; Individual; Inflammatory; Intervention Studies; Late Effects; Maintenance; Malignant Neoplasms; Metabolic Pathway; Metabolism; Minnesota; Modeling; Molecular Epidemiology; Morbidity - disease rate; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Play; Population; Prostate; Public Health; Recurrent disease; Relapse; Reporting; Research; Risk; Role; Second Primary Cancers; Serum; Signal Transduction; Single Nucleotide Polymorphism; Specimen; Sterols; Survival Rate; Tissues; Transplantation; Treatment Effectiveness; Treatment outcome; United States; Universities; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein; Vitamin D3 Receptor; Work; cancer therapy; cost effective; gene environment interaction; genetic analysis; genetic profiling; genetic variant; graft vs host disease; hazard; improved; innovation; interest; long term hospitalization; mortality; nutrition

DESCRIPTION (provided by applicant): For the more than 40,000 people who receive blood and marrow transplantations (BMT) worldwide each year, treatment related morbidity and mortality especially graft-vs-host disease (GVHD), disease relapse and treatment related mortality, remains a substantial concern. Because of its immunomodulatory and cell cycle regulatory activities, maintaining adequate vitamin D status throughout the treatment course may decrease risk of GVHD and disease relapse, which in turn, could result in improved survival rates compared to individuals who are vitamin D deficient. Little is known about vitamin D status during BMT, although there is reason to believe that vitamin D deficiency is common. The long-term goal is to understand how nutrition interventions can be used to minimize the toxic side effects of cancer treatment, enhance the effectiveness of treatment, and decrease the late-effects of cancer treatment. The objective of this project, is to determine the extent to which genetic variation in the vitamin D biosynthesis pathway is associated with treatment outcome in the BMT population. The central hypothesis is that genetic variation in the vitamin D biosynthesis and metabolism pathways influences vitamin D status, especially on a local, tissue-specific level, and thus can alter risk of acute GVHD, disease relapse, and survival. Gene-environment interactions are often present in metabolic pathways, with genetic effects being most prominent in the setting of deficiency of key pathway substrates. The rationale for the proposed research is that if a particular genetic profile within the vitamin D metabolic pathway is found to be associated with adverse BMT outcomes, it would be possible to identify high-risk individuals prior to transplant, and follow them closely to maintain adequate vitamin D status. The specific aim of this project is to determine the extent to which genetic variants, or combinations of genotypes, in the vitamin D metabolic pathway (CYP2R1, CYP3A4, CYP27A1, CYP27B1, vitamin D binding protein, and CYP24A1) are associated with risk of acute GVHD, disease relapse, and survival among individuals who have undergone allogeneic BMT for treatment of hematologic malignancies. Using existing treatment related data from the University of Minnesota BMT database and stored biospecimens, this project will include 750 patients who received an allogeneic BMT at the University of Minnesota between 1995 and 2005, and their donors. A total of 58 single nucleotide polymorphisms (SNPs) in genes involved in vitamin D biosynthesis, transport, signaling and catabolism will be evaluated in both patient and donor specimens. Proportional hazard multivariable regression modeling will be used to evaluate associations between candidate SNPs, combinations of SNPs, and haplotypes and risk of acute GVHD, disease relapse, survival and disease free survival. This study will be the first to comprehensively evaluate the association between genetic variation in the entire vitamin D biosynthesis pathway and BMT outcomes. At the end of this project, we expect to have preliminary data for a future intervention study to evaluate the effect of maintenance of adequate vitamin D levels on BMT outcomes. PUBLIC HEALTH RELEVANCE Despite significant advances in treatment outcomes for hematologic malignancies over the past 40 years, blood and marrow transplantation (BMT) is associated with high treatment related morbidity, prolonged hospitalizations, and long-term health problems. This study will determine the extent to which genetic variation in the vitamin D biosynthesis pathway is associated with treatment outcomes (specifically risk of graft-vs-host disease, disease relapse, and survival). If a particular genetic profile within the vitamin D metabolic pathway is found to be associated with adverse BMT outcomes, it would be possible to identify high-risk individuals prior to transplant and work to maintain adequate vitamin D status throughout the treatment course in order to minimize adverse outcomes.

描述（由申请人提供）： 对于全世界每年超过 40,000 人接受血液和骨髓移植 (BMT) 的人来说，治疗相关的发病率和死亡率，特别是移植物抗宿主病 (GVHD)、疾病复发和治疗相关的死亡率，仍然是一个重大问题。由于其免疫调节和细胞周期调节活性，在整个治疗过程中保持足够的维生素 D 状态可能会降低 GVHD 和疾病复发的风险，从而与缺乏维生素 D 的个体相比，可能会提高生存率。尽管有理由相信维生素 D 缺乏很常见，但对 BMT 期间维生素 D 的状况知之甚少。长期目标是了解如何利用营养干预措施来最大限度地减少癌症治疗的毒副作用，提高治疗的有效性，并减少癌症治疗的后期影响。该项目的目标是确定维生素 D 生物合成途径的遗传变异与 BMT 人群的治疗结果相关的程度。核心假设是，维生素 D 生物合成和代谢途径的遗传变异会影响维生素 D 状态，尤其是在局部、组织特异性水平上，从而改变急性 GVHD、疾病复发和生存的风险。基因-环境相互作用通常存在于代谢途径中，其中遗传效应在关键途径底物缺乏的情况下最为突出。拟议研究的基本原理是，如果发现维生素 D 代谢途径中的特定基因谱与不良 BMT 结果相关，则可以在移植前识别高风险个体，并密切跟踪他们以保持足够的维生素 D 状态。该项目的具体目的是确定维生素 D 代谢途径（CYP2R1、CYP3A4、CYP27A1、CYP27B1、维生素 D 结合蛋白和 CYP24A1）中的遗传变异或基因型组合与急性维生素 D 风险的相关程度。接受同种异体 BMT 治疗血液恶性肿瘤的个体的 GVHD、疾病复发和生存率。该项目利用明尼苏达大学 BMT 数据库的现有治疗相关数据和存储的生物样本，包括 1995 年至 2005 年间在明尼苏达大学接受同种异体 BMT 的 750 名患者及其捐赠者。将在患者和供体样本中评估涉及维生素 D 生物合成、转运、信号传导和分解代谢的基因中总共 58 个单核苷酸多态性 (SNP)。比例风险多变量回归模型将用于评估候选 SNP、SNP 组合和单倍型与急性 GVHD、疾病复发、生存和无病生存风险之间的关联。这项研究将首次全面评估整个维生素 D 生物合成途径的遗传变异与 BMT 结果之间的关联。在该项目结束时，我们期望获得未来干预研究的初步数据，以评估维持足够的维生素 D 水平对 BMT 结果的影响。公共健康相关性 尽管过去 40 年来血液系统恶性肿瘤的治疗结果取得了显着进步，但血液和骨髓移植 (BMT) 仍与治疗相关的高发病率、长期住院治疗和长期健康问题相关。这项研究将确定维生素 D 生物合成途径中的遗传变异与治疗结果（特别是移植物抗宿主病、疾病复发和生存的风险）的相关程度。如果发现维生素 D 代谢途径中的特定基因谱与不良 BMT 结果相关，则可以在移植前识别高风险个体，并努力在整个治疗过程中保持足够的维生素 D 状态，以最大程度地减少不良后果。