Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis

Abstract

Although single nucleotide polymorphisms (SNPs) in folate-mediated pathways predict susceptibility to choline deficiency during severe choline deprivation, it is unknown if effects persist at recommended intakes. Thus, we used stable isotope liquid chromatography-mass spectrometry (LC-MS) methodology to examine the impact of candidate SNPs on choline metabolism in a long-term, randomized, controlled feeding trial among pregnant, lactating, and nonpregnant (NP) women consuming 480 or 930 mg/d choline (22% as choline-d, with d indicating a deuterated trimethyl amine group) and meeting folate-intake recommendations. Variants impairing folate metabolism, methylenetetrahydrofolate reductase (MTHFR) rs1801133, methionine synthase (MTR) rs1805087 [wild-type (WT)], MTR reductase (MTRR) rs1801394, and methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) rs2236225, influenced choline dynamics, frequently through interactions with reproductive state and choline intake, with fewer genotypic alterations observed among pregnant women. Women with these variants partitioned more dietary choline toward phosphatidylcholine (PC) biosynthesis via the cytidine diphosphate (CDP)-choline pathway at the expense of betaine synthesis even when use of betaine as a methyl donor was increased. Choline intakes of 930 mg/d restored partitioning of dietary choline between betaine and CDP-PC among NP (MTHFR rs1801133 and MTR rs1805087 WT) and lactating (MTHFD1 rs2236225) women with risk genotypes. Overall, our findings indicate that loss-of-function variants in folate-metabolizing enzymes strain cellular PC production, possibly via impaired folate-dependent phosphatidylethanolamine-N-methyltransferase (PEMT)-PC synthesis, and suggest that women with these risk genotypes may benefit from choline intakes exceeding current recommendations.-Ganz, A. B., Shields, K., Fomin, V. G., Lopez, Y. S., Mohan, S., Lovesky, J., Chuang, J. C., Ganti, A., Carrier, B., Yan, J., Taeswuan, S., Cohen, V. V., Swersky, C. C., Stover, J. A., Vitiello, G. A., Malysheva, O. V., Mudrak, E., Caudill, M. A. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis.

Dietary choline levels modify the effects of prenatal alcohol exposure in rats

“…For example, dietary choline needs may be affected by genetic variations in phosphatidylethanolamine N -methyltransferase (PEMT) (da Costa et al, 2006) or methylenetetrahydrofolate dehydrogenase (MTHFD) (Kohlmeier et al, 2005). Even genetic variation in folate needs may also affect required dietary choline levels (Ganz et al, 2016). If reductions in dietary choline availability increase risk for FASD, it is likely that individuals with genetic polymorphisms that require more dietary choline may be at higher risk for having a child with FASD if they drink during pregnancy.…”

Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations

“…Endpoint genotyping was carried out as previously described using participant DNA and two commercially available products, (Applied Biosystems TaqMan Genotyping Master Mix and Thermo Fisher Scientific Assay Mix, Waltham, MA, USA) on a LightCycler 480 (Roche) in our facility [9]. …”

“…Enrichments of methionine-d 3 were measured by gas chromatography-mass spectrometry (GC-MS) [9]. Enrichment percentages were calculated by dividing the area of each isotopically labeled choline metabolite by the total area of all isotopomers and multiplying by 100% (Equation (1)).…”

Common Genetic Variants Alter Metabolism and Influence Dietary Choline Requirements

“…After week six, 22% of choline was provided as deuterium labeled choline chloride-(trimethyl-d 9 ), a metabolic tracer that enables tracking of dietary choline throughout different metabolic pathways and compartments such as blood, urine, and breast milk. This allows for elucidation of the effects of various factors (e.g., reproductive state, choline intake, genetic variation) on the metabolic flux and partitioning of dietary choline [ 22 , 23 , 24 ]. With regard to genetic variation, Ganz et al [ 23 , 24 ] assessed the impact of loss-of-function SNPs in folate and choline metabolizing genes.…”

“…This allows for elucidation of the effects of various factors (e.g., reproductive state, choline intake, genetic variation) on the metabolic flux and partitioning of dietary choline [ 22 , 23 , 24 ]. With regard to genetic variation, Ganz et al [ 23 , 24 ] assessed the impact of loss-of-function SNPs in folate and choline metabolizing genes. The folate SNPs, which included MTHFR rs1801133, methionine synthase ( MTR ) rs1805087 (wildtype), methionine synthase reductase ( MTRR ) rs1801394, and MTHFD1 rs2236225, were all found to influence choline dynamics, frequently through interactions with reproductive state and choline intake [ 23 ] ( Figure 2 ).…”