Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (44), p.16025-16030
• Main Authors: Kohlmeier, M, da Costa, K.A, Fischer, L.M, Zeisel, S.H
• Format: Article
• Language: English
• Subjects: 5,10-methylenetetrahydrofolate dehydogenase; 5,10-methylenetetrahydrofolate reductase; adenosylhomocysteine; Adult; Aged; Alleles; binding proteins; Biological Sciences; Carbon - metabolism; choline; Choline - administration & dosage; Choline deficiency; Choline Deficiency - drug therapy; Choline Deficiency - etiology; Choline Deficiency - genetics; deficiency diseases; Dehydrogenases; Diet; Enzymes; Female; folate carrier 1; folic acid; Folic Acid - administration & dosage; Folic Acid - metabolism; Genetic Predisposition to Disease; genetic variation; Genetics; Genotypes; Heterozygote; Humans; Liver; Male; Medical research; Men; Metabolism; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Middle Aged; Minerals; mutants; nutrient deficiencies; nutritional status; organ dysfunction; oxidoreductases; Polymorphism; Polymorphism, Genetic; Premenopause; Ratios; single nucleotide polymorphism; Statistical significance; Tetrahydrofolates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0504285102

Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0-25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement. The effects of the C677T and A1298C polymorphisms of the 5,10-methylene tetrahydrofolate reductase gene and the A80C polymorphism of the reduced folate carrier 1 gene were not statistically significant. The most remarkable finding was the strong association in pre-menopausal women of the 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele polymorphism with 15 times increased susceptibility to developing organ dysfunction on a low-choline diet.