Start Date: Feb 11, 2009
End Date: Feb 10, 2014
In this project, we will use multiple approaches to study the biochemistry and molecular biology of the interaction of B vitamins with each other and their role in modulating the risk for age-related pathologies, and the genetic factors that influence these interactions. We will determine the interaction between vitamin B12 status, unmetabolized folic acid, methyl tetrahydrofolate and folic acid intake in relation to cognitive impairment, bone mineral density, cardiovascular disease risk, diabetes and cancer. For this purpose, we will measure the unmetabolized folic acid and methyl folate in the plasma of participants in National Health and Nutrition Examination Survey 1999-2002 and Framingham Heart Study (FHS) Offspring cohorts, measure plasma concentration of methylmalonic acid (MMA) in FHS Offspring cycle 7 examinations and use plasma MMA as a marker of vitamin B12 status. We will also use an animal model of vitamin B12 deficiency to characterize the biochemical and hematological effect of high folate status under vitamin B12 deficiency. The gene-nutrient interaction between folate and the 677C>T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene will be studied by determining the changes in DNA methylation and gene expression using microarray analysis after a 3-month dietary supplementation of 400µg/day folic acid in individuals homozygous for the C and T alleles of the MTHFR polymorphism. The heritability of plasma homocysteine concentration in FHS cohort will be determined by comparing data on plasma homocysteine from 3 generations of FHS participants in the context of their plasma folate and vitamin B12 status, and by determining the association between polymorphisms in genes that influence methylation of homocysteine including those involved in uptake of vitamin B12, and plasma homocysteine concentration.