CHOLINE

Choline is an essential nutrient required for the structural integrity of cell membranes and signaling functions, methyl group metabolism and neurotransmitter synthesis. People who eat choline-deficient diets develop fatty liver, liver damage, and muscle damage (Kozyreva, O. G. et al., 2006). It is also suggested that choline plays a critical role in fetal development and that pregnancy significantly increases the mother's choline needs (Ivanov, A. et al., 2009). The best dietary sources of choline include liver, eggs and wheat germ. In foods, choline is found free and as choline esters. It is not clear whether a normal diet provides the recommended amount of choline for all people. The only source of choline outside the diet is the de novo biosynthesis of phosphatidylcholine catalyzed by phosphatidylethanolamine- N -methyltransferase (PEMT) in the liver (Zeisel, S. H., 2007).

 

What is the MTHFD1 Gene?

5, 10-methylenetetrahydrofolate dehydrogenase (MTHFD1), a folate-dependent enzyme, has a central role in folate metabolism. In addition to its enzymatic activity, MTHFD1 has also been shown to play a critical role in methionine synthesis and as a structural component in de novo purine and pyrimidine synthesis (Jiang, J. et al., 2014).

 

What is the PEMT Gene?

Endogenous biosynthesis of choline in the liver occurs when phosphatidylethanolamine is methylated by phosphatidylethanolamine N-methyltransferase (PEMT) to form phosphatidylcholine. The PEMT enzyme is also encoded by the PEMT gene. PEMT activity is responsible for the endogenous biosynthesis of the choline moiety, and this activity is increased by estrogen treatment (Kozyreva, O. G. et al., 2006).

CHOLINE
Genes	rs	Minor Allele	Minor Allele Description	Reference
MTHFD1	rs2236225	T	High relative risk for Choline requirement, possibly due to decreased enzyme activity.	(Ganz, A. B. et al., 2016)
PEMT	rs7946	T	High relative risk for Choline requirement, possibly due to decreased PEMT activity.	(Song, J. et al., 2005)

The table above contains genes and polymorphisms related to Choline metabolism. The MTHFD1 rs2236225 polymorphism encodes an enzyme with a ~50% reduction in enzymatic activity. This variant also increases susceptibility to choline deficiency in premenopausal women who are deficient in choline. It shows that the MTHFD1 rs2236225 variant may increase susceptibility to choline and phosphodithylcholine deficiency even at choline intakes consistent with current recommendations (Ganz, A. B. et al., 2016). 

rs7946 polymorphism causes loss of function in the PEMT enzyme. With this variant, the risk of fatty liver disease increases when the diet is inadequate in choline (Song, J. et al., 2005).

 

REFERENCES

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. (2016). Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. The FASEB Journal, 30(10), 3321-3333. https://doi.org/10.1096/fj.201500138RR

Ivanov, A., Nash-Barboza, S., Hinkis, S., & Caudill, M. A. (2009). Genetic variants in phosphatidylethanolamine N-methyltransferase (PEMT) and methylenetetrahydrofolate dehydrogenase (MTHFD1) influence biomarkers of choline metabolism when folate intake is restricted. Journal of the American Dietetic Association, 109(2), 313. https://doi.org/10.1016/j.jada.2008.10.046

Jiang, J., Zhang, Y., Wei, L., Sun, Z., & Liu, Z. (2014). Association between MTHFD1 G1958A Polymorphism and Neural Tube Defects Susceptibility: A Meta-Analysis. PLoS ONE, 9(6). https://doi.org/10.1371/journal.pone.0101169

Kozyreva, O. G., Song, J., Galanko, J. A., Fischer, L. M., & Zeisel, S. H. (2006). Common genetic polymorphisms affect the human requirement for the nutrient choline. The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 20(9), 1336. https://doi.org/10.1096/fj.06-5734com

Song, J., Fischer, L. M., Kohlmeier, M., Kwock, L., Wang, S., & Zeisel, S. H. (2005). Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 19(10), 1266. https://doi.org/10.1096/fj.04-3580com

Zeisel, S. H. (2007). Gene Response Elements, Genetic Polymorphisms and Epigenetics Influence the Human Dietary Requirement for Choline. IUBMB Life, 59(6), 380. https://doi.org/10.1080/15216540701468954