Progress 10/15/08 to 10/14/13
Outputs
Target Audience:To close project as PD is terminated from university. 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?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
To close project as PD is terminated from university.
Publications
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Progress 10/01/10 to 09/30/11
Outputs
OUTPUTS: Objective 1 was partially finalized including the evaluation of the effect of folic acid intervention by dose and genotype on DNA methylation response in Chinese women of reproductive age. Data from a comparison study evaluating the impact of the source of DNA (clot vs whole blood) were reanalyzed and included in the primary paper related to the effect of folic acid on DNA methylation. Major differences in DNA methylation were found that were dependent on the source of DNA (blood clot vs blood). Data from this series of investigations in Chinese women were reanalyzed and journal publications revised, resubmitted, and accepted for publication. DNA methylation response by genotype in women of reproductive age in Honduras were reanalyzed and manuscript preparation initiated. Results related to a new analytical approach to determine DNA methylation in diluted blood samples were incorporated into the manuscript. The results indicated that exposure to folic acid supplementation did not influence DNA methylation in these women. The influence of the MTHFR polymorphism on DNA methylation was assessed and found not to have a significant impact. Progress was made toward the completion of Objective 2, which is to investigate the influence of vitamin B12 status and polymorphisms on DNA methylation in Chinese women of reproductive age. Data were reanalyzed and the manuscript preparation initiated. Progress towards completion of Objective 3 was made including the transfer of DNA samples from post-menopausal women from the University of Florida to Cornell University where the methylation analysis will now take place. The methylation analysis was initiated by collaborators at Cornell with final results anticipated in the upcoming year. PARTICIPANTS: Dr. Lynn B. Bailey, Co-PI, directed the DNA methylation projects, assisted with manuscript preparation and review of manuscripts; co-developed proposals and assisted with contract negotiations to determine DNA methylation and genetic polymorphisms in blood samples collected in China, Honduras, and the US. Served as group leader in the planning, implementation, and report of findings relative to all studies. Dr. Gail P. A. Kauwell, Co-PI for the Honduras study was involved in all aspects of study design, data analysis, and report of findings relative to DNA methylation and genotype effect. David R. Maneval, Research Coordinator, coordinated research activities for DNA methylation and genotyping studies. Dr. Jorge Rosenthal, CDC/CCHP/NCBDDD, CDC collaborator and contact for research being conducted using samples obtained from a Honduran population. Dr. Krista Crider, CDC/CCHP/NCBDDD, served as a collaborator and project consultant as well as manuscript preparation. Dr. RJ Berry, CDC collaborator and project consultant for DNA methylation studies. Marie Caudill, Cornell University, conducted DNA methylation analyses for Objective 3 involving post-menopausal women. Centers for Disease Control and Prevention provided funding for certain components of the research plan. The University of Georgia has become a partner with the relocation of Dr. Lynn B. Bailey to this institution. Cornell University has been added as a partner organization because the DNA methylation analysis for Objective 3 is being conducted at Cornell University. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The findings from Objective 1 of this series of investigations indicate that DNA methylation results differ between blood sample types and that the clotting process significantly affects DNA methylation. These results have implications for investigators who are planning to conduct DNA methylation analysis on different sample types. The findings from this investigation also provide the framework for future investigations to determine how the clotting process may impact DNA methylation. The finding that the presence of a genetic polymorphism affecting the folate pathway may significantly impact DNA methylation response to folic acid supplementation indicates that an individual's genetic profile may significantly influence gene-nutrient interactions. Our successful innovative analytical approaches to extract sufficient DNA from diluted samples will provide guidance to other investigators whose goal it is to retrospectively determine DNA methylation changes in samples that were previously considered unacceptable for this type of analysis due to low DNA yields using traditional extraction techniques. Our finding that folic acid supplementation does not impact DNA methylation is important for government approval of folic acid intervention programs in Honduras and other countries in Central America. These programs would be in jeopardy if the data had indicated that DNA methylation was significantly impacted by folic acid intake. Since DNA methylation may have potential negative effects on health including growth abnormalities and chronic diseases, the finding that folic acid had no effect removes this potential road block to folic acid intervention in Central America. The analysis and interpretation of data relative to folate and vitamin B12 status of women of reproductive age in China will provide the basis on a new intervention program designed to reduce anemia in this high-risk group. Recommended nutrient intakes for pregnant women provide guidance to clinicians and to women regarding adequate intake of essential nutrients associated with optimal pregnancy outcomes.
Publications
- Crider KS, Quinlivan EP, Berry RJ, Hao L, Li Z, Maneval D, Yang TP, Rasmussen SA, Yang Q, Zhu J-H, Hu DJ, Bailey, LB. Genomic DNA methylation changes in response to folic acid supplementation in a population-based intervention study among women of reproductive age. PLoS ONE 6(12): e28144.doi:10.1371/journal.pone.0028144, 2011.
- Crida K, Zhu J-H, Ling H, Yang Q-H, Yang T, Gindler, J, Maneval DR, Quinlivan EP, Li Z, Bailey LB, Berry RJ. Methylenetetrahydrofolate reductase 677C→T genotype is associated with folate and homocysteine concentration in a large population-based double-blind trial of folic acid supplementation. Am J Clin Nutr 93: 1365, 2011.
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Progress 10/01/09 to 09/30/10
Outputs
OUTPUTS: A research proposal/contract was written and submitted to the Centers for Disease Control and Prevention (CDC) to investigate the influence of blood sample type on DNA methylation results. A DNA methylation study was completed to compare the results obtained using DNA extracted from blood clots compared to DNA extracted from unclotted blood. Major differences in DNA methylation were found that were dependent on the source of DNA (blood clot vs blood). Data analysis was completed to assess the impact of the MTHFR polymorphism on blood folate response to folic acid supplementation in Chinese women of reproductive age. Different analytical approaches were developed to extract sufficient DNA from diluted blood samples collected in Honduras from women involved in a folic acid intervention study. The new analytical approaches to determine DNA methylation were successfully implemented. The results indicated that exposure to folic acid supplementation did not influence DNA methylation in these women. Genotyping for the MTHFR polymorphism was completed on blood samples collected from women in the Honduras folic acid intervention study. The influence of the MTHFR polymorphism on DNA methylation was assessed and found not to have a significant impact. Collaborative plans were made with coinvestigators of the Women's Health Initiative study to conduct DNA methylation analysis of samples collected from women who were being evaluated for risk of colorectal cancer. Data analysis was completed and a manuscript was prepared that described the influence of vitamin B12 status on global DNA methylation based on analysis on DNA extracted from blood clots and blood cells collected in young Chinese women. A collaborative study was undertaken with CDC investigators to estimate folic acid intake of the US population and to determine the contribution of specific sources to folic acid intake as well as the percentage of the population that consume levels of folic acid that exceed recommendations. A collaborative study was completed with Chinese investigators to interpret folate and vitamin B12 status data in relationship to anemia in women of childbearing age in a rural area of northern China. A joint collaboration with clinicians in the obstetrics and gynecology field involved a detailed review of published literature and development of recommendations for nutrient intakes for pregnant women and women planning to become pregnant. A review of scientific evidence related to the chemical and physiological differences between folic acid and 5-methytetrahydrofolic acid was conducted. PARTICIPANTS: Individuals: Dr. Lynn B. Bailey, Co-PI, directed the DNA methylation projects, assisted with manuscript preparation and review of manuscripts; co-developed proposals and assisted with contract negotiations to determine DNA methylation and genetic polymorphisms in blood samples collected in China, Honduras, and the US. Served as group leader in the planning, implementation, and report of findings relative to all studies. Dr. Gail P. A. Kauwell, Co-PI for the Honduras study was involved in all aspects of study design, data analysis, and report of findings relative to DNA methylation and genotype effect. David R. Maneval, Research Coordinator, coordinated research activities for DNA methylation and genotyping studies. Dr. Jorge Rosenthal, CDC/CCHP/NCBDDD , CDC collaborator and contact for research being conducted using samples obtained from a Honduran population. Dr. Krista Crider, CDC/CCHP/NCBDDD, served as a collaborator and project consultant. Dr. RJ Berry, CDC collaborator and project consultant for DNA methylation studies. Partner Organizations: Centers for Disease Control and Prevention provided funding for certain components of the research plan. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
IMPACT The findings of this study indicate that DNA methylation results differ between blood sample types and that the clotting process significantly affects DNA methylation. These results have implications for investigators who are planning to conduct DNA methylation analysis on different sample types. The findings from this investigation also provide the framework for future investigations to determine how the clotting process may impact DNA methylation. The finding that the presence of a genetic polymorphism affecting the folate pathway may significantly impact DNA methylation response to folic acid supplementation indicates that an individual's genetic profile may significantly influence gene-nutrient interaction. Our successful innovative analytical approaches to extract sufficient DNA from diluted samples will provide guidance to other investigators whose goal it is to retrospectively determine DNA methylation changes in samples that were previously considered unacceptable for this type of analysis due to low DNA yields using traditional extraction techniques. The finding that young children in the US have much higher folic acid intakes than recommended will be translated into advice for parents of young children. The finding that the source of folic acid that leads to excess intake of folic acid in adults and young children is supplements will be translated into advice for parents of children, clinicians, and consumers. Our finding that folic acid supplementation does not impact DNA methylation is important for government approval of folic acid intervention programs in Honduras and other countries in Central America. These programs would be in jeopardy if the data had indicated that DNA methylation was significantly impacted by folic acid intake. Since DNA methylation may have potential negative effects on health including growth abnormalities and chronic diseases, the finding that folic acid had no effect removes this potential road block to folic acid intervention in Central America. The analysis and interpretation of data relative to folate and vitamin B12 status of women of reproductive age in China will provide the basis on a new intervention program designed to reduce anemia in this high-risk group. Recommended nutrient intakes for pregnant women provide guidance to clinicians and to women regarding adequate intake of essential nutrients associated with optimal pregnancy outcomes. The evaluation of differences in the commercially available chemical forms of folate provides guidance to consumers and the pharmaceutical industry who are considering the use of either form as a supplement or food fortificant.
Publications
- Krista S Crider, Eoin P Quinlivan, Robert J Berry, Ling Hao, Zhu Li, David Maneval, Thomas P Yang, Sonja A Rasmussen, Quanhe Yang, Jiang-Hui Zhu, Dale J Hu, Lynn B Bailey. 2010. Genomic DNA methylation changes in response to folic acid supplementation and withdrawal in a population-based intervention study among women of reproductive age― differential response in coagulated vs. uncoagulated blood. J Nutr (submitted).
- Krista S. Crider, Jiang-Hui Zhu, Ling Hao, Quan-He Yang, Thomas P. Yang, Jacqueline Gindler, David R. Maneval, Eoin P. Quinlivan, Zhu Li, Lynn B. Bailey, Robert. J. Berry. 2010. Methylenetetrahydrofolate reductase 677C→T genotype is associated with folate and homocysteine concentration in a large population-based double-blind trial of folic acid supplementation. AJCN (in press)
- Yeung LF, Cogswell ME, Carriquiry A, Bailey LB, Pfeiffer CM, Berry RJ. 2010 Contributions of enriched cereal grain products, ready-to-eat cereal, and supplements to the folic acid and vitamin B12 status in US children: National Health and Nutrition Examination Survey (NHANES) 2003-2006. Am J Clin Nutr 93:1-14.
- Yang Q, Cogswell, ME, Hamner H, Carriquiry A, Bailey LB, Pfeiffer CM, Berry RJ. 2010. Folic acid source, usual intake, and folate and vitamin B12 status in US adults: National Health and Nutrition Examination Survey, 2003-2006. Am J Clin Nutr 91:64-72.
- Jiang Hui Zhu, Dale J. Hu, Ling Hao, Bao Lan Zhang, Mary E. Cogswell, Lynn B. Bailey, Zhu Li and R.J. Berry. 2010. Iron, folate, and B12 deficiencies and their associations with anemia among women of childbearing age in a rural area in northern China. Int J Vit Nut Res 80: 144-54.
- Pietrzik, K, Bailey, LB., Shane B. 2010. Folic acid and L-5-methyltetrahydrofolate: Comparison of Clinical Pharmacokinetics and Pharmacodynamics. Clinical Pharmacokinetics 49: 535-48.
- Simpson JL, Bailey, LB, Shane B, Holzgreve W, Pietrzik K. 2010. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I-Folates, Vitamin B12, Vitamin B6. J Maternal-Fetal and Neonatal Medicine. 23: 1323-43.
- Simpson JL, Bailey, LB, Shane B, Holzgreve W, Pietrzik K. 2010. 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 Maternal-Fetal and Neonatal Medicine. DOI: 10.3109/14767051003678226. Early Online 1-24.
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Progress 10/01/08 to 09/30/09
Outputs
OUTPUTS: Completed data analysis and prepared a manuscript describing the results related to genotype-dependent global DNA methylation response to folic acid based on analysis done on DNA extracted from blood clots collected in young Chinese women. Presented findings at Experimental Biology meeting related to genotype effects on DNA methylation. Presented findings at Experimental Biology meeting related to effect of folic acid on gene-specific methylation changes. Completed data analysis and prepared a manuscript describing the influence of vitamin B12 status on global DNA methylation based on analysis on DNA extracted from blood clots collected in young Chinese women. Completed a DNA methylation study to compare the results obtained using DNA extracted from blood clots compared to DNA extracted from blood. Found major differences in DNA methylation that were dependent on source of DNA (blood clot vs blood). Investigated different analytical approaches to extract sufficient DNA from diluted blood samples collected in Honduras for DNA methylation analysis. Completed analysis of genotype data to determine the influence of the MTHFR 677C>T polymorphism on blood folate and homocysteine concentrations in Chinese women Collaborated with CDC investigators to estimate folic acid intake of the US population, determined the contribution of specific sources to folic acid intake, and the percentage of the population that are consuming levels of folic acid that exceed recommendations Coauthored a publication for a major nutrition journal related to folic acid intake in the US Coauthored a book chapter that presented recommended folate intakes, consumption, and status for the US Edited a book with >50 scientific expert authors related to folate in health and disease Conducted a webinar for the USDA Dietary Guidelines Advisory Committee related to folate intake and associated health outcomes PARTICIPANTS: Dr. Lynn B. Bailey, Co-PI, directed the DNA methylation projects, assisted with manuscript preparation and review of manuscripts; co-developed a proposal and assisted with contract negotiations to determine serum folate concentrations from samples collected in two African countries; co-developed and submitted proposals to investigate the analytical validity of a new methodological approach for determining the folate and vitamin B12 content from dried blood spots; spear-headed preliminary plans to investigate the influence of folate-related genetic polymorphisms on folate status from samples obtained from women participating in a randomized controlled folic acid intervention study; co-authored a book chapter related to folate intake and status; edited a book on folate in health and disease. Dr. Gail P. A. Kauwell, Co-PI, assisted with manuscript preparation and review for two manuscripts; co-developed a proposal and assisted with contract negotiations to determine serum folate concentrations from human blood samples collected in two African countries; co-developed and submitted proposals to investigate the analytical validity of a new methodological approach for determining the folate and vitamin B12 content from dried blood spots; co-authored a book chapter related to folate intake and status. David R. Maneval, Research Coordinator, coordinated research activities for DNA methylation studies and assisted with the development of a proposal and to determine serum folate concentrations from human blood samples collected in two African countries; assisted with the development of proposals to investigate the analytical validity of a new methodological approach for determining the folate and vitamin B12 content from dried blood spots. Centers for Disease Control and Prevention provided funding for certain components of the research plan. National Fisheries Institute provided funding for certain components of the research plan. PATH - potential collaborator on a project designed to develop and test new methods for determining folate and vitamin B12 status. Global Alliance for Improved Nutrition (GAIN) Dr. Kristina von Castel-Roberts, Department of Clinical and Health Psychology, University of Florida, co-authored one manuscript and assisted with manuscript preparation and review of a second manuscript. Dr. Mustafa Vakur Bor, Department of Clinical Biochemistry, Aarhus University Hospital, AS, Denmark: Conducted data analysis and co-authored one of two manuscripts. Dr. Ebba Nexo, Department of Clinical Biochemistry, Aarhus University Hospital, AS, Denmark, assisted with interpretation of data and manuscript preparation and review for one of two manuscripts. Dr. Sally P. Stabler, Denver and Health Sciences Center, Aurora, CO, reviewed and approved one of two final manuscripts. Dr. Jorge Rosenthal, CDC/CCHP/NCBDDD , CDC collaborator and contact for research being conducted using samples obtained from a Honduran population. Dr. Krista Crider, CDC/CCHP/NCBDDD, served as a collaborator and project consultant. Dr. RJ Berry, CDC collaborator and project consultant for DNA methylation studies. Training or professional development N/A for these projects TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The finding that the presence of a genetic polymorphism affecting the folate pathway may significantly impact DNA methylation response to folic acid supplementation indicates that an individual's genetic profile may significantly influence gene-nutrient interaction. Since DNA methylation is linked to differences in gene expression, these observations provide the rationale to investigate the effect of genetic polymorphisms on DNA methylation of specific genes involved in health maintenance as well as disease and birth defect prevention. Our research group is the first to compare DNA methylation changes in DNA extracted from blood clots vs blood. Our initial finding of differences serves as the basis for an upcoming large-scale comparison study to definitively characterize the magnitude of the differences in DNA methylation determined in DNA extracted from blood clots vs blood cell fraction. These data will provide researchers with evidence that the source of DNA may influence the interpretation of how folic acid affects DNA methylation status. These findings provide the rationale for future investigations to determine what factors associated with the clotting process impact DNA methylation. Innovative analytical approaches to extract sufficient DNA from diluted samples will provide guidance to other investigators whose goa it is to retrospectively determine DNA methylation changes in samples that were previously considered unacceptable for this type of analysis due to low DNA yields using traditional extraction techniques. Presentations were made at multiple state, national, and international scientific meetings to share scientific research findings Presentations were made at state and national conferences of health care practitioners regarding interpretation of research findings for health maintenance and disease and birth defect prevention Presentations were made to government agencies (USDA, CDC) and public health related organizations (March of Dimes) involved in developing guidelines and public health programs to ensure adequate folate intake consistent with current research findings for health maintenance and disease/birth defect prevention
Publications
- Jason O. Brant, Jianghui Zhu, Krista Crider, R.J. Berry, Ling Hao, Zhu Li, David Maneval, Lynn B. Bailey, Thomas P. Yang 2009. Analysis of Locus-Specific DNA Methylation in Response to Chronic Folic Acid Supplementation and Withdrawal in Chinese Women. FASEB J.
- Rampersaud GC, Kauwell GPA, Bailey, LB, Sargent SMJ, Brennan MM 2009. Development and evaluation of a folic acid education program for the worksite. Proceedings of 6th International Nutrition Conference.
- Referred Journal papers Zhu J, Hao L, Li S, Bailey LB, Tian Y, Li Z 2009. MTHFR, TGFB3, and TGFA polymorphisms and their association with the risk of non-syndromic cleft lip and cleft palate in China. Am J Medical Genetics Part A 9999:1-9.
- Q.-H. Yang, M. Cogswell, H. Hamner, A. Carriquiry, C. Pfeiffer, L. B. Bailey and R. Berry 2009 Usual intake of folic acid from different sources and association with tolerable upper intake level, folate, and vitamin B12 status among US adults: findings from the National Health and Examination Survey 2001-2004. Am J Clin Nutr (in press, Epub ahead of print Oct 14. DOI:10.3945/ajcn.2009.28401).
- Hardlei TF, Moerkbak AL, Bor MV, Bailey LB, Hvas A-M, Nexo E 2009 Assessment of vitamin B12 absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin. Clinical Chemistry (in press).
- Pietrzik, K, Bailey, L. B., Shane B 2009. Folic acid and L-5-methyltetrahydrofolate: Comparison of Clinical Pharmacokinetics and Pharmacodynamics. Cinical Pharmacokinetics, (in press).
- Von Castel-Roberts, K.M., Whittmann, A.R., Maneval, D.R., Bailey, L.B., Kauwell, G.P.A 2009 Contribution of seafood to total vitamin B12 intake and status of young adult men and women. Journal of Aquatic Food Product Technology (in press)
- Bor M-V, von Castel-Roberts K M , Kauwell, GPA, Stabler SP, Allen RH 3 , Maneval DR , Bailey LB, and Nexo E 2009 Daily intake of 4 to 7 micrograms of dietary vitamin B12 is associated with steady levels of vitamin B12-related biomarkers in a healthy young population, Am J Clin Nutr (in press).
- Book Chapter Kauwell, G.P.A., Diaz, M.L., Bailey, L.B 2010. Folate recommended intakes, consumption, and status, Chapter 19 In L.B. Bailey (ed), Folate in Health and Disease. CRC Press Taylor & Francis Group. Boca Raton, FL, p.467-490.
- Book edited Folate in Health and Disease, 2nd Ed, Bailey, LB 2009 (ed), Taylor and Francis, CRC press, pgs 1-583.
- Abstracts Eoin Quinlivan, Krista Crider, RJ Berry, Ling Hao, Zhu Li, Jianghui Zhu, David Maneval, Gail Kauwell, and Lynn B. Bailey 2009. Associations of folate status and methylenetetrahydrofolate reductase (MTHFR) 677CT polymorphism with global DNA methylation in US and Chinese women. FASEB J.
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