Progress 10/01/08 to 10/01/11
Outputs
OUTPUTS: In biologial samples obtained from men differing in a common genetic variant in a folate metabolizing gene (MTHFR) gene, we quantified a panel of endpoints related to methyl metabolism including: leukocyte global DNA methylation; serum vitamin B-12 concentrations; plasma concentrations of S-adenosylmethionine and S-adenosylhomocysteine; plasma riboflavin concentrations; genotypes of genes that encode enzymes with key roles in methyl metabolism (i.e., PEMT, MTR, MTRR, MTHFD1); and biomarkers of choline metabolism. We also prepared manuscripts for publication. PARTICIPANTS: Individuals that worked on the project include: 4 undergraduate students, a visiting scholar (Nelle Dellschaft), 6 masters level students, 1 doctoral student (Jian Yan), 1 biostatistician, 2 laboratory technicians, and 5 collaborating investigators. The 5 collaborating investigators were: Tom Brenna at Cornell University; Wei Wang at Cal Poly Pomona University; Jesse F. Gregory III at University of Florida; and Sally P. Stabler and Robert H. Allen at the University of Colorado Health Sciences Center. This project trained students on several laboratory techniques related to genotyping (DNA extraction, purification, sequencing as well as restriction fragment length polymorphism techniques). The visiting scholar and PhD student were also trained on liquid chromatography-mass spectrometry methodology including sample extraction, clean-up, standard preparations, and operation of the LC-MC. The graduate student and visiting scholar also worked with our statistical consulting unit to run all of the statistics that were used in our analysis of the data. The visiting scholar and PhD student were also mentored on developing and writing the manuscripts for publication. TARGET AUDIENCES: Target Audiencies include: nutritionists and clinicians working in health care settings and/or research areas that focus on reducing the risk of diseases associated with methyl group nutrients (i.e., choline, folate, riboflavin and vitamin B-12); and research/clinical scientists serving on the Food and Nutrition Board of the Institute of Medicine charged with developing dietary recommendations that meet the needs of 97% of a healthy population. Data from this study emphasize the importance of considering genetic background when establishing dietary intake recommendations for choline. PROJECT MODIFICATIONS: No Major changes
Impacts
Our findings clearly show that homozygosity for a common variant in a folate metabolizing enzyme (MTHFR) increases the use of choline as a methyl donor and modifies genomic and metabolic endpoints that are disease antecedants. Men with this variant need more choline and possibly other methyl donors to achieve genomic and metabolic endpoints comparable to their wildtype counterparts. We also showed that the variant in the MTHFR gene interacts with other genetic variants to modify homocysteine, an indicator of compromised methyl group metabolism, and a risk factor for numerous chronic diseases.
Publications
- Caudill MA, Dellschaft N, Solis C, Hinkis S, Ivanov AA, Nash-Barboza S, Randall KE, Jackson B, Solomita GN, Vermeylen F (2009). Choline intake, plasma riboflavin and the PEMT G5465A genotype predict plasma homocysteine in folate deplete Mexican American men with the MTHFR 677TT genotype. J Nutr. 139:727-733
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Progress 10/01/09 to 09/30/10
Outputs
OUTPUTS: This years activities included assessing the impact of the MTHFR 677TT genotype on choline turnover in this group of Mexican American men. In the original study, the men consumed deuterium labeled choline chloride. Thus we were able to measure the enrichment of the choline metabolites in plasma and urine and determine whether the MTHFR 677TT genotype modulated choline flux through 1-C metabolic pathways. These data were analyzed and submitted for publication. Also we made the necessary modifications to have our previously submitted paper (Shin et al. 2010) accepted and published in Journal of Nutrition. PARTICIPANTS: The individuals that worked on these projects included Jian Yan (predoctoral student at Cornell University) and Amanda Lusa (Undergraduate student at Cornell University). Olga Malysheva, the lab manager, also assisted with measurements and supervision of project. TARGET AUDIENCES: Nutritionists, clinicians and scientists serving on the committee that develops dietary recommendations are the target audience. Data from this study highlight the importance of considering genetic background when assessing choline requirements. PROJECT MODIFICATIONS: Project expanded to include assessments of the enriched choline metabolites.
Impacts
Our findings showed the choline metabolism is different in men with the MTHFR 677TT genotype such that they use more choline as a methyl donor. These findings imply that individuals with the 677TT genotype have a higher dietary requirement for choline than those with the 677TT genotype.
Publications
- Shin W, Yan J, Abratte CF, Vermeylen F, and Caudill MA (2010). Choline intake exceeding current dietary recommendations preserves markers of cellular methylation in a genetic sub-group of folate-compromised men. J Nutr 140:975-980.
- Yan J, Wang W, Gregory JF III, Malysheva OV, Brenna JT, Stabler SP, Allen RH, Caudill MA (2011). MTHFR C677T genotype influences the isotopic enrichment of one carbon metabolites in folate compromised men consuming d9-choline. Am J Clin Nutr. 2011;93:348-55.
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Progress 10/01/08 to 09/30/09
Outputs
OUTPUTS: The main activites performed throughout this reporting period included measurements of global DNA methylation in samples obtained from Mexican American men consuming varied choline intakes (n=60), and measuring plasma riboflavin, vitamin B-12 and S-adenosylmethionine and S-adenosylhomocysteine. Other activies included data analysis and manuscript preparation. PARTICIPANTS: My laboratory technician set up the DNA methylation assay and measured leukocyte global DNA methylation in duplicate in all the collected samples. My undergraduate student, Amanda Lusa, who worked on the uracil misincorporation assay. TARGET AUDIENCES: These samples were obtained from Mexican American men (n=60). The generated data therefore will be most relevant to this specific ethnic group. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Data thus far show that choline significantly modifies biomarkers of one-carbon metabolism alone, and together with, other B-vitamins and common genetic variants.
Publications
- Shin W, Yan J, Abratte CF, Vermeylen F, and Caudill MA.(2010)Choline intakes at amounts exceeding current dietary recommendations beneficially influence markers of cellular methylation in a genetic sub-group of folate deplete men. (submitted).
- Caudill MA, Dellschaft N, Solis C, Hinkis S, Ivanov AA, Nash-Barboza S, Randall KE, Jackson B, Solomita GN, Vermeylen F. (2009) Choline intake, plasma riboflavin and the PEMT G5465A genotype predict plasma homocysteine in folate deplete Mexican American men with the MTHFR 677TT genotype. J Nutr. 2009;139:727-733
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