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，与治疗相关的发病率和死亡率，特别是移植物抗宿主病(GVHD)、疾病复发和与治疗相关的死亡率，仍然是一个令人严重关切的问题。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状态可能会降低移植物抗宿主病和疾病复发的风险，这反过来又可以提高与维生素D缺乏的人相比的存活率。尽管有理由相信维生素D缺乏症很常见，但人们对BMT期间维生素D的状况知之甚少。长期目标是了解如何使用营养干预将癌症治疗的毒副作用降至最低，提高治疗的有效性，并减少癌症治疗的后遗症。该项目的目标是确定在骨髓移植人群中维生素D生物合成途径的遗传变异与治疗结果相关的程度。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的状态，特别是在局部的组织特异性水平上，因此可以改变急性移植物抗宿主病、疾病复发和生存的风险。基因与环境的相互作用经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。这项拟议研究的基本原理是，如果维生素D代谢途径中的特定基因图谱被发现与不利的BMT结果相关，则有可能在移植前识别高危个体，并密切跟踪他们，以保持足够的维生素D状态。该项目的具体目标是确定维生素D代谢途径中的遗传变异或基因组合(CYP2R1、CYP3A4、CYP27A1、CYP27B1、维生素D结合蛋白和CYP24A1)与急性移植物抗宿主病(GVHD)风险、疾病复发和接受异基因骨髓移植治疗恶性血液病患者的生存相关程度。利用明尼苏达大学骨髓移植数据库中现有的治疗相关数据和储存的生物样本，该项目将包括在1995年至2005年期间在明尼苏达大学接受异基因骨髓移植的750名患者及其捐赠者。涉及维生素D生物合成、转运、信号和分解代谢的58个单核苷酸多态(SNPs)将在患者和捐赠者样本中进行评估。比例风险多变量回归模型将用于评估候选SNPs、SNPs组合和单倍型与急性移植物抗宿主病(GVHD)、疾病复发、存活率和无病存活率之间的关系。这项研究将首次全面评估整个维生素D生物合成途径中的遗传变异与骨髓移植结果之间的关联。在该项目结束时，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水平对骨髓移植结果的影响。公共卫生相关性尽管在过去40年中，血液和骨髓移植(BMT)在治疗恶性血液病方面取得了显著进展，但它与治疗相关的高发病率、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疾病、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的骨髓移植结果有关，则有可能在移植前识别高危个体，并努力在整个治疗过程中保持足够的维生素D状态，以最大限度地减少不良后果。

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.