Genetic Variation in Vitamin D Metabolism and BMT Outcomes

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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.