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Modulation of the Homocysteine-Betaine Relationship by Methylenetetrahydrofolate Reductase 677 C->T Genotypes and B-Vitamin Status in a Large-Scale Epidemiological Study

Hormone Laboratory (P.I.H., S.H.), Haukeland University Hospital, Bergen 5021, Norway; LOCUS for Homocysteine and Related Vitamins (P.M.U., J.S.), Institute of Medicine, University of Bergen, 5021 Bergen, Norway; LOCUS for Homocysteine and Related Vitamins (S.E.V.), Department of Public Health and Primary Health Care, University of Bergen, 5021 Bergen, Norway; Cancer Registry of Norway (T.G.), Institute of Population-Based Cancer Research, Montebello, 0310 Oslo, Norway

Address all correspondence and requests for reprints to: Per Magne Ueland, Section for Pharmacology, Institute of Medicine, Armauer Hanssens hus, University of Bergen, 5021 Bergen, Norway. E-mail: per.ueland{at}ikb.uib.no.

Context: Betaine is formed from the essential nutrient choline or is supplied from the diet. It serves as a substrate in the betaine-homocysteine methyltransferase reaction and thereby provides methyl groups for the homocysteine-methionine cycle, which is regulated by enzymes dependent on folate, vitamin B12, riboflavin (vitamin B2), or vitamin B6.

Objective: We investigated how betaine affected total homocysteine (tHcy) concentration within the frame of variable B-vitamin status and according to the methylenetetrahydrofolate reductase (MTHFR) 677C->T genotype.

Design/Setting/Patients: This is a population-based study with a cross-sectional design. It includes 10,601 healthy men and women aged 50–64 yr.

Outcome Measures: Plasma samples were analyzed for tHcy, betaine, choline, dimethylglycine, riboflavin, and vitamin B6, whereas folate and vitamin B12 were analyzed in serum.

Results: Betaine was a strong determinant of plasma tHcy in subjects with low serum folate and the MTHFR TT genotype. The association was further strengthened at low levels in the circulation of the other B-vitamins (B2, B6, and B12). Thus, in subjects with the combination of serum folate in the lowest quartile, low vitamin B2, B6, and B12 status, and the MTHFR TT genotype, the difference in tHcy (mean, 95% confidence interval) across extreme plasma betaine quartiles was 8.8 (1.3–16.2) µmol/liter.

Conclusion: Betaine may thus be an important one-carbon source, particularly in MTHFR 677 TT subjects with inadequate B-vitamin status.