The MTHFR Gene & Methylation (Part 1 of 3)
Methylation is a vital metabolic process that occurs in every cell and organ of the body.[i] The metabolic reactions that occur during methylation generate numerous different substances in the body, including that of adenosine triphosphate (ATP) – the energy unit of our body’s cells![ii]
The MTHFR polymorphism (multiple variations of a single gene) limits the methylation of folate (vitamin B9) and vitamins B6 and B12 in the body. When methylation is compromised, homocysteine levels rise. Elevated homocysteine levels are associated with increased risk for stroke, cardiovascular disease[iii], Alzheimer’s disease, dementia[iv], Parkinson’s Disease[v], migraines[vi] and other conditions.
Research has demonstrated that strategic supplementation can reduce homocysteine levels. One particular study found that supplementation with 2 mg of folic acid, 25 mg of vitamin B6 and 400 µg of vitamin B12 for six months reduced homocysteine levels in the body by 39%.[vii] Individuals with MTHFR polymorphism C677>TT (homozygous) showed less of a decline in their homocysteine levels than those with heterozygotes or wild type genotypes, yet still showed improvement.
Similarly, a five-year study looked at the MTHFR genotype categories in those with a history of cardiovascular disease that were supplemented with 560 µg of 5-methyl-THF (the biologically active form of folate), 3 mg of vitamin B6 and 20 µg of vitamin B12.[viii] Although all MTHFR genotypes initially experienced a large decrease in homocysteine levels and increase in B vitamins, as time progressed, the homocysteine levels of the TT genotype increased slightly more than other genotypes.
A different group of researchers considered the same polymorphisms over 4.5 years of supplementation with folic acid and discovered that 0.8 mg/day increased all genotypes (with the exception of the T or TT variants) to optimal levels.[ix] They noted that there was a threshold effect on homocysteine levels when folate serum levels were raised to 15 ng/mL across all genotypes. In other words, after the folate serum levels reached 15ng/mL, more had nearly no effect on homocysteine levels. These results taken together suggested that maybe folic acid therapy should be individualized to a person’s genotype or folate serum status.
In Part 2 of this blog post series, we further explore how strategic forms of supplementation can support the above-noted nutrients when impaired methylation is an issue.
[i] Kresser, C. (2014, September 11). RHR: Methylation – What Is It and Why Should You Care? Retrieved from https://chriskresser.com/methylation-what-is-it-and-why-should-you-care/
[ii] Kresser, C. (2014, September 11). RHR: Methylation – What Is It and Why Should You Care? Retrieved from https://chriskresser.com/methylation-what-is-it-and-why-should-you-care/
[iii] Li, Y., Huang, T.,Zheng, Y., Muka, T., Troup, J., & Hu,. F. B. (2016). Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc.; doi: 10.1161/JAHA.116.003768
[iv] Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D’Agostino, R.B., et al. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med, 346: 476–83.
[v] Vallelunga, A., Pegoraro, V., Pilleri, M. Biundo, R., De luliis, A., Marchetti, M.,& …. Antonini, A. (2014). The MTHFR C677T polymorphism modifies age at onset in Parkinson’s disease. Neurol Sci, 35: 73. https://doi-org.uws.idm.oclc.org/10.1007/s10072-013-1545-z
[vi] Lea, R.A., Colson, N.J., Quinlan, S.K., Macmillan, J.C., & Griffiths, L.R. (2009). The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenetics and genomics, 19 6, 422-8.
[vii] Lea, R.A., Colson, N.J., Quinlan, S.K., Macmillan, J.C., & Griffiths, L.R. (2009). The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenetics and genomics, 19 6, 422-8.
[viii] Fezeu LK, Ducros V, Guéant J-L, Guilland J-C, Andreeva VA, Hercberg S, & Galan, P. (2018) MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial. PLoS ONE 13(5): e0193352. https://doi.org/10.1371/journal.pone.0193352
[ix] Huang, X., Xianhui, Q., Wenbin, Y., Lishun, L., Chongfei, J., Xianglin, Z., & …. Xiaoshu, C. (2018). MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(3): 679–685