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. 2005 Nov 1;102(44):16025-30.
doi: 10.1073/pnas.0504285102. Epub 2005 Oct 18.

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

Martin Kohlmeier  1 , Kerry-Ann da Costa, Leslie M Fischer, Steven H Zeisel
Affiliations

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

Martin Kohlmeier et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Fig. 1.
Fig. 1.
Three polymorphic genes are critical for folate-mediated one-carbon transfer. THF, tetrahydrofolate; MTHFR, 5,10-methylene tetrahydrofolate reductase; MTHFD1, cytosolic 5,10-methylene tetrahydrofolate dehydrogenase; RFC1, reduced folate carrier 1.
Fig. 2.
Fig. 2.
Increase in SAH concentrations after a methionine load was lower in MTFD1 1958 GG individuals. Subjects were treated with a low-choline diet as described in Methods. Blood for SAM and SAH measurements was obtained before (fasting) and 4 h after an oral methionine load (Met-load; 100 mg of l-methionine per kg of body weight) from 26 individuals with MTHFD1 1958 GA/AA genotype and from 15 individuals with MTHFD1 1958 GG genotype. Values are presented as mean ± standard error. Solid bars indicate means of individuals with the MTHFD1 1958 GA or AA genotypes, and open bars correspond to means from those with the GG genotype. *, P < 0.05; **, P < 0.01 different from other genotype by one-way ANOVA.
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