Genetic Variation in Vitamin D Metabolism and BMT Outcomes

描述（由申请人提供）： 对于全世界每年接受血液和骨髓移植（BMT）的40，000多人来说，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，这反过来又可能导致与维生素D缺乏的个体相比提高生存率。关于BMT期间维生素D的状况知之甚少，尽管有理由相信维生素D缺乏症很常见。长期目标是了解如何使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。该项目的目的是确定维生素D生物合成途径中的遗传变异与BMT人群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影响维生素D状态，特别是在局部组织特异性水平上，因此可以改变急性GVHD，疾病复发和生存的风险。基因-环境相互作用经常存在于代谢途径中，在关键途径底物缺乏的情况下，遗传效应最为突出。这项研究的基本原理是，如果发现维生素D代谢途径中的特定遗传特征与不良BMT结果相关，则有可能在移植前识别出高风险个体，并密切关注他们以保持足够的维生素D状态。本项目的具体目的是确定维生素D代谢途径（CYP 2 R1、CYP 3A 4、CYP 27 A1、CYP 27 B1、维生素D结合蛋白和CYP 24 A1）中的遗传变异或基因型组合与接受异基因BMT治疗恶性血液病的个体中急性GVHD、疾病复发和生存风险的相关程度。利用明尼苏达大学BMT数据库中现有的治疗相关数据和储存的生物标本，该项目将包括1995年至2005年在明尼苏达大学接受同种异体BMT的750例患者及其供体。将在患者和供体标本中评价涉及维生素D生物合成、转运、信号传导和催化剂的基因中的共58个单核苷酸多态性（SNP）。将使用比例风险多变量回归建模来评价候选SNP、SNP组合和单倍型与急性GVHD风险、疾病复发、存活和无病存活之间的关联。这项研究将是第一项全面评估整个维生素D生物合成途径中的遗传变异与BMT结果之间的关联的研究。在本项目结束时，我们希望为未来的干预研究提供初步数据，以评估维持足够的维生素D水平对BMT结果的影响。尽管在过去的40年中血液恶性肿瘤的治疗结果取得了显著进展，但血液和骨髓移植（BMT）与高治疗相关发病率、长期住院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）相关的程度。如果发现维生素D代谢途径中的特定遗传特征与不良BMT结果相关，则可以在移植前识别高风险个体，并在整个治疗过程中保持足够的维生素D状态，以最大限度地减少不良结果。

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.