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）： 对于每年在全球接受血液和骨髓移植（BMT）的40,000多人来说，与治疗相关的发病率和死亡率，尤其是Graft-VS-host疾病（GVHD），疾病复发和与治疗相关的死亡率，仍然是一个实质性的关注。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，这反过来又可能会提高生存率，而维生素D不足的人则可能会提高生存率。尽管有理由相信维生素D缺乏症是常见的，但对BMT期间的维生素D状态知之甚少。长期目标是了解如何使用营养干预措施来最大程度地减少癌症治疗的毒性副作用，提高治疗的有效性并降低癌症治疗的晚期效果。该项目的目的是确定维生素D生物合成途径中的遗传变异与BMT种群中的治疗结果有关。中心假设是维生素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，因此可以改变急性GVHD的风险，疾病复发和存活。基因环境相互作用通常存在于代谢途径中，遗传效应在关键途径底物缺乏的情况下最为突出。拟议的研究的理由是，如果发现维生素D代谢途径内的特定遗传特征与不良BMT结局有关，则可以在移植前识别高危个体，并密切关注它们以维持足够的维生素D状态。该项目的具体目的是确定维生素D代谢途径中遗传变异或基因型的组合的程度（CYP2R1，CYP3A4，CYP27A1，CYP27A1，CYP27B1，CYP27B1，VITAMIN D，维生素D的结合蛋白和CYP24A1）与急性GVHD相对症的风险相关，并与之相关。血液学恶性肿瘤的治疗。使用明尼苏达大学BMT数据库的现有相关数据并存储了生物测量，该项目将包括1995年至2005年之间在明尼苏达大学接受同种异体BMT的750名患者，及其捐助者。在患者和供体标本中，将评估共有58种单核苷酸多态性（SNP），其中涉及维生素D生物合成，运输，信号和分解代谢的基因。比例危害多变量回归建模将用于评估候选SNP，SNP和单倍型组合与急性GVHD，疾病复发，生存和无疾病生存的风险之间的关联。这项研究将是第一个全面评估整个维生素D生物合成途径中的遗传变异与BMT结果之间的关联。在该项目结束时，我们希望有初步的数据进行以后的干预研究，以评估维持适当维生素D水平对BMT结果的影响。公共卫生相关性尽管在过去40年中血液学恶性肿瘤的治疗结果取得了重大进展，但血液和骨髓移植（BMT）仍与高治疗相关的发病率，长时间住院和长期健康问题有关。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有关（特别是治疗疾病的风险，疾病复发和生存）。如果发现维生素D代谢途径内的特定遗传特征与不良BMT结果有关，则可以在移植前识别高危个体并在整个治疗过程中保持适当的维生素D状态，以最大程度地减少不良结果。