Progress 10/01/08 to 09/30/13
Outputs
Target Audience: Nutritional scientists and policy makers. Information provides through classroom teaching, lectures at scientific meetings and workshops, and publications in the scientific literature. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?
Nothing Reported
How have the results been disseminated to communities of interest? This work has been disseminated by publications in the scientific literature and by talks at scientific meeetings such as the 9th International Homocysteine and One Carbon Metabolism meeting in Dublin (2013) where I was invited to give the opening address. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. Although it has been suggested that folate fortification exacerbates vitamin B12 deficiency symptoms, our recent studies on the Trinity Student cohort do not support any adverse effects of folate fortification on vitamin B12 status in a young population. Our genetic studies may suggest novel biomarkers for assessing vitamin status. New mechanism have been identified that may explain why B12 deficiency can lead to neurological symptoms and how increased folate intake may exacerbate symptoms of B12 deficiency. We have also identified genetic variations in the human genome that influence plasma and red cell folate levels.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
Shane, B. (2013). Folate and vitamin B12 function. In Encyclopedia of Biological Chemistry, Lennarz, W. and Lane, M. D., eds., 2nd ed., pp. 324-328, Elsevier, New York.
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Progress 01/01/12 to 12/31/12
Outputs
OUTPUTS: We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. PARTICIPANTS: Barry Shane, Ph.D., principal investigator TARGET AUDIENCES: Nutritional scientists and policy makers. Information provides through classroom teaching, lectures at scientific meetings and workshops, and publications in the scientific literature. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. Although it has been suggested that folate fortification exacerbates vitamin B12 deficiency symptoms, our recent studies on the Trinity Student cohort do not support any adverse effects of folate fortification on vitamin B12 status in a young population. Our genetic studies may suggest novel biomarkers for assessing vitamin status.
Publications
- Pangilinan, F., Molloy, A. M., Mills, J. L., Troendle, J. F., Parle-McDermott, A., Signore, C. C., O'Leary, V., Chines, P., Dolle, J., Geiler, K., Mitchell, A., VanderMeer, J., Krebs, K. M., Sanchez, A., Cornman-Homonoff, J., Stone, N., Conley, M., Kirke, P. N., Shane, B., Scott, J. M. and Brody, L. C. (2012). Evaluation of Common Genetic Variants in 82 Candidate Genes as Risk Factors for Neural Tube Defects. BMC Medical Genetics 13: 29 (http://www.biomedcentral.com/1471-2350/13/29).
- Caudill, M. A., Miller, J. W., Gregory, J. F. III and Shane, B. Folate, choline, vitamin B12, and vitamin B6. (2012) In Biochemical, Physiological and Molecular Aspects of Human Nutrition, Stipanuk, M. H. and Caudill, M. A., eds., third edition, chapter 25, pp. 565-609, Elsevier, New York.
- Shane, B. (2012). Folate-responsive birth defects: of mice and women. Am. J. Clin. Nutr. 2012; 95:1-2.
- Schaevitz, L. S., Picker, J. D., Rana, J., Kolodny, N. H., Shane, B., Berger-Sweeney, J.E. and Coyle, J.T. (2012). Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders. Dev. Neurobiol. 72: 891-905. doi: 10.1002/dneu.21000.
- Anderson, D. A., Woeller, C. F., Chiang, E.P., Shane, B. and Stover, P. J. (2012). SHMT anchors the de novo thymidylate synthesis pathway to the nuclear lamina for DNA synthesis. J Biol Chem. 287: 7051-7062.
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Progress 01/01/11 to 12/31/11
Outputs
OUTPUTS: We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. PARTICIPANTS: Barry Shane, Ph.D., principal investigator TARGET AUDIENCES: Nutritional scientists and policy makers. Information provides through class room teaching, lectures at scientific meetings and workshops, and publications in the scientific literature. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. Although it has been suggested that folate fortification exacerbates vitamin B12 deficiency symptoms, our recent studies on the Trinity Student cohort do not support any adverse effects of folate fortification on vitamin B12 status in a young population. Our genetic studies may suggest novel biomarkers for assessing vitamin status.
Publications
- Neuhouser ML, Nijhout HF, Gregory JF III, Reed MC, James SJ, Liu A, Shane B, Ulrich CM. (2011). Mathematical modeling predicts the effect of folate deficiency and excess on cancer related biomarkers. Cancer Epidemiol. Biomark. Prev. 20: 1912-1917.
- Stone N, Pangilinan F, Molloy AM, Shane B, Scott JM, Ueland PM, Mills JL, Kirke PN, Sethupathy P, Brody LC. (2011). Bioinformatic and genetic association analysis of microRNA target sites in one-carbon metabolism genes. PLoS ONE 2011;6(7):e21851.
- Mills JL, Carter TC, Scott JM, Troendle JF, Gibney ER, Shane B, Kirke PN, Ueland PM, Brody LC, Molloy AM. (2011). Do high blood folate concentrations exacerbate the metabolic abnormalities in people with low vitamin B12 status? Am. J. Clin. Nutr. 94: 495-500.
- Shane B. (2011). Folate status assessment history: implications for measurement of biomarkers in the National Health and Nutrition Examination Survey. Am. J. Clin. Nutr. 94: 337-42S.
- Yetley EA, Pfeiffer CM, Phinney KW, et al. (2011). Biomarkers of folate status in NHANES. A Roundtable summary. Am. J. Clin. Nutr. 94: 303-12S.
- Yetley EA, Pfeiffer CM, Phinney KW, et al. (2011). Biomarkers of vitamin B-12 status in NHANES. A Roundtable summary. Am. J. Clin. Nutr. 94: 313-21S.
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Progress 01/01/10 to 12/31/10
Outputs
OUTPUTS: We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylenetetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. PARTICIPANTS: Barry Shane, Ph.D., principal investigator. TARGET AUDIENCES: Nutritional scientists and policy makers. Information provides through class room teaching, lectures at scientific meetings and workshops, and publications in the scientific literature. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. Although it has been suggested that folate fortification exacerbates vitamin B12 deficiency symptoms, our recent studies on the Trinity Student cohort do not support any adverse effects of folate fortification on vitamin B12 status in a young population.
Publications
- Bagley P, Shane B. (2010). Folate. In Encyclopedia of Dietary Supplements, Coates P, Betz JM, Blackman MR, Cragg GM, Levine M, Moss J, White JD, eds., 2nd ed., pp. 288-77, Informa Healthcare, New York.
- Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I--Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med 2010;23(12):1323-43. doi: 10.3109/14767051003678234 [doi].
- Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2010;49(8):535-48. doi: 10.2165/11532990-000000000-00000 [doi]
- Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part II--vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids. J Matern Fetal Neonatal Med 2011;24(1):1-24. doi: 10.3109/14767051003678226 [doi].
- Carter TC, Pangilinan F, Troendle JF, et al. Evaluation of 64 candidate single nucleotide polymorphisms as risk factors for neural tube defects in a large Irish study population. Am J Med Genet A 2011;155A(1):14-21. doi: 10.1002/ajmg.a.33755 [doi].
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Progress 01/01/09 to 12/31/09
Outputs
OUTPUTS: We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: Knowledge applied to undergraduate and graduate teaching and lectures presented at scientific meeting and university departments. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification.
Publications
- Shane, B. (2009) Folate chemistry and metabolism. In Folate in Health and Disease, Bailey, L. B., ed., Clinical Nutrition in Health and Disease Series, 2nd ed., pp. 1-24, CRC Press, New York.
- Pietrzik, K., Bailey, L. and Shane, B. (2010) Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin. Pharmacokin. (in press)
- MacFarlane, A.J., Perry, C. A., Girnary, H. H., Gao, D., Allen,, R. H., Stabler,, S. S., Shane, B. and Stover, P. J. (2009). Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism. J. Biol. Chem. 284:1533-1539.
- Simpson, J. L., Bailey, L. B., Pietrzik, K., Shane, B. and Holzgreve, W. (2010) Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. I: Folate, vitamin B12, vitamin B6. J. Maternal-Fetal Neonat. Med. (in press)
- Simpson, J. L., Bailey, L. B, Pietrzik, K., Shane, B. and Holzgreve, W. (2010) Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. II: Vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids. J. Maternal-Fetal Neonat. Med. (in press)
- Bagley, P. and Shane, B. (2010). Folate. In Encyclopedia of Dietary Supplements, Coates, P., Blackman, M. R., Cragg, G., Levine, M., Moss, J. and White, J., eds., 2nd ed., Marcel Dekker, New York (in press).
- Nan Wang (2009) Ph.D. thesis. Molecular and Biochemical Nutrition, UCB. Phenotypic studies in mice deficient in methylenetetrahydrofolate reductase and methionine synthase and their use as models for the pathophysiology of vitamin B12 deficiency.
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