title: Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans.
abstract: 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 premenopausal 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.
authors.affiliation: Department of Nutrition, School of Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kohlmeier
authors.forename: Kerry-Ann
authors.initials: KA
authors.lastname: da Costa
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Fischer
authors.forename: Steven H
authors.initials: SH
authors.lastname: Zeisel
mesh_terms: D000328:Adult; D000368:Aged; D002244:Carbon / Q000378:metabolism*; D002794:Choline / Q000008:administration & dosage; D002796:Choline Deficiency / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017697:Premenopause
chemical_list: D002244:Carbon; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D002794:Choline