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

Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16025-30. doi: 10.1073/pnas.0504285102. Epub 2005 Oct 18.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Carbon / metabolism*
  • Choline / administration & dosage
  • Choline Deficiency / drug therapy
  • Choline Deficiency / etiology
  • Choline Deficiency / genetics*
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / metabolism*
  • Genetic Predisposition to Disease*
  • Heterozygote
  • Humans
  • Male
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics
  • Middle Aged
  • Polymorphism, Genetic*
  • Premenopause


  • Carbon
  • Folic Acid
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Choline