MTHFR - May the Cycle Be Unbroken

We often take for granted the elaborate processes that keep us in good health. However, when something goes wrong, we are reminded of the fragile and complicated nature of the human body. 

The slightest change to the hidden cycles that make us tick can complicate our lives or upend them completely. 

One of these processes is called the methylation cycle. Many people have never heard of it, but this cycle and the protein methylenetetrahydrofolate reductase (MTHFR) play a central role in human health.

 

What is MTHFR?

MTHFR is a protein at the heart of the methylation cycle, a process that is integral to cardiovascular, brain, liver, and reproductive health1. The methylation cycle is a series of reactions our cells perform that help control our metabolism, DNA production, circadian rhythms, and much more. Living things ranging from single-celled algae to humans all rely on this cycle2. 

Methylation is the addition of a single carbon atom attached to three hydrogen atoms. This small change has substantial effects on how proteins, DNA, and fats behave in our bodies, dramatically impacting our wellbeing. Methylation and demethylation, the opposite process, produce the raw ingredients for energy, new DNA, and more3.

In addition, MTHFR helps convert the different forms of folate, also called vitamin B91,3-5, which is necessary for brain development during pregnancy. In doing so, it helps control levels of the amino acid homocysteine. Homocysteine plays important biological roles, but high levels are associated with increased risk of pregnancy complications, stroke, cardiovascular disease, and deep vein thrombosis4,6. 

MTHFR’s job in the methylation cycle is to convert the inactive form of folate, 5,10-MTHF, into the active version, 5-MTHF. Then, the enzyme methionine synthase uses 5-MTHF to convert harmful homocysteine into the amino acid methionine, which has several uses in the body. 

During this process, MTHFR changes 5-MTHF into tetrahydrofolic acid (THF), which is needed to produce new DNA for dividing cells, like those in the skin, gut, hair follicles, and blood5,6. A supplement like Methyl Folate 5-MTHF™ Drops that provides extra 5-MTHF may promote a healthy methylation cycle and better wellbeing.

 

How can MTHFR mutations affect me?

Since MTHFR is central to the methylation cycle and making new DNA, mutations can have profound health consequences. Therefore, learning about your unique set of SNPs through Holistic Health International’s DNA Nutrigenomic Test is essential to your individual wellness journey. 

This testing kit was carefully designed by Dr. Yasko to identify harmful mutations and comes with individualized analysis based on her research into genetics and nutrition. Our nutrigenomic testing can tell you if you have the most prevalent MTHFR mutations, two single nucleotide polymorphisms (SNPs) called C677T and A1298C1. 

 

What is an SNP?

DNA, the backbone of life, is a linked strand of chemicals called nucleotides that are often represented with the letters A, T, C, and G. The order of the nucleotides in a gene acts as a code that tells cells how to build proteins. 

An SNP describes a single nucleotide that is changed or missing. Sometimes, an SNP does not have any real effects. When one does, however, the results can range from harmless to lethal7. 

SNPs for the MTHFR gene weaken the function of MTHFR, causing harmful levels of homocysteine and increased risk of congenital disabilities1. Reinforcing weak points in the methylation cycle with our Full Methylation Cycle Support may promote wellbeing by targeting these processes.

 

MTHFR C677T

The C677T SNP is the most common MTHFR mutation and is associated with more aggressive and malignant forms of breast cancer, although it doesn’t increase the overall risk of the disease1,8,9. In addition, people with major depressive disorders are more likely to have this variant10. Nutrigenomic testing to detect whether you have the C677T variant provides essential information to guide you and your wellness team.

MTHFR A1298C

The A1298C SNP is less common and is more prevalent in European populations1. People with the A1298C SNP are more likely to develop non-alcoholic fatty liver disease, although this risk can be reduced with proper medical care and nutritional management11. Just like the C677T variant, breast cancer patients with this SNP are more likely to have an aggressive form of the disease8. 

How are MTHFR, homocysteine, and heart disease linked?

High homocysteine levels cause damaging changes to the heart and blood vessels12. Homocysteine can damage the cells lining blood vessels and make it harder for them to contract and dilate. This stiffens the arteries and worsens high blood pressure. As a result, homocysteine levels are tied to the severity of coronary disease13. 

Additionally, the harmful effects of smoking could be worsened by elevated homocysteine12. Some studies have shown that folic acid supplementation lowers the risk of cardiovascular disease and stroke5,14. 

There is also a potential link between MTHFR SNPs and congenital heart disorders. Evidence suggests that C677T and A1298C can significantly increase the risk of congenital heart defects15,16.  However, more work is needed to draw firm conclusions9,17. Regardless, for those already at risk for cardiovascular disease, supporting the methylation cycle with products like our Folinic +™ Capsules can provide peace of mind.

 

How do MTHFR mutations increase the risk of miscarriage?

MTHFR and the methylation cycle were working within you before you even had a brain. Early in pregnancy, the entire nervous system starts off as a flat sheet of cells18. This sheet eventually rolls up into the neural tube, which later becomes the brain and spinal cord18. If the neural tube does not close correctly, it can cause birth defects ranging from minor to fatal19,20. 

For example, neural tube closure defects can result in anencephaly, where the skull doesn’t close, and the brain fails to develop19,20. Anencephaly is always lethal. Spina bifida occulta is a neural tube defect that often has no symptoms and isn’t diagnosed until adulthood19,20. 

Folate is required for neural tube closure21. Since high homocysteine levels in people with MTHFR SNPs can result in low folate, these SNPs are associated with neural tube defects and pregnancy loss3,22,23. Accordingly, research has confirmed that early pregnancy loss is increased in people with either SNP. It is, however, significantly higher in individuals with the C677T SNP23 . 

Fortunately, appropriate prenatal care can reduce the risk of miscarriage in people with either SNP to normal levels23. One study showed that a combination of low-dose aspirin, enoxaparin, and folic acid helped reduce miscarriages in women with C677T SNPs and a history of repeated pregnancy loss24. 

 

How can I test for MTHFR SNPs?

Since the effects of MTHFR mutations can go undetected for a long time, many of us likely have a variant gene without even knowing it. Therefore, DNA testing is required to identify which, if any, MTHFR SNP you may carry.

At Holistic Health, we offer a DNA Nutrigenomic Test with analysis from Dr. Amy Yasko, the creator of The Yasko Protocol for autism and fatigue. This can identify weak points in your methylation cycle, including any MTHFR variants, and point you towards supplements and nutritional plans that may support your wellbeing.  

Where can I get supplements to support my methylation cycle?

We provide several high-quality supplements, like our MTHFR A1298C+ Liver Support Capsules, Methyl Folate 5-MTHF Mega Drops™, and comprehensive All in One™ Multi-Vitamin / Mineral Capsules. 

Our products are not a replacement for expert medical care from your doctor and nutritionist. However, our supplements targeting the methylation cycle can give you and your care team a powerful tool for your journey to good health. 

Contact us today or visit us at www.holisticheal.com to find the supplements and testing supplies to meet your unique nutritional needs.

References

1. Leclerc D SS, Rozen R. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms. Madame Curie Bioscience Database [Internet].  Austin (TX): Landes Bioscience; 2000-2013.
2. Fustin JM, Ye S, Rakers C, et al. Methylation deficiency disrupts biological rhythms from bacteria to humans. Commun Biol. 2020;3(1):211.
3. Dean L. Methylenetetrahydrofolate Reductase Deficiency. In: Pratt VM, Scott SA, Pirmohamed M, et al., eds. Medical Genetics Summaries. Bethesda (MD)2012.
4. Cao H, Hu X, Zhang Q, et al. Hyperhomocysteinaemia, low folate concentrations and MTHFR C677T mutation in abdominal aortic aneurysm. Vasa. 2014;43(3):181-188.
5. Wan L, Li Y, Zhang Z, Sun Z, He Y, Li R. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry. 2018;8(1):242.
6. Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1):e6-9.
7. Shastry BS. SNPs: impact on gene function and phenotype. Methods Mol Biol. 2009;578:3-22.
8. Castiglia P, Sanna V, Azara A, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in breast cancer: a Sardinian preliminary case-control study. Int J Med Sci. 2019;16(8):1089-1095.
9. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci. 2001;22(4):195-201.
10. Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005;19(1):59-65.
11. Catalano D, Trovato GM, Ragusa A, et al. Non-alcoholic fatty liver disease (NAFLD) and MTHFR 1298A > C gene polymorphism. Eur Rev Med Pharmacol Sci. 2014;18(2):151-159.
12. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015;14:6.
13. Shenoy V, Mehendale V, Prabhu K, Shetty R, Rao P. Correlation of serum homocysteine levels with the severity of coronary artery disease. Indian J Clin Biochem. 2014;29(3):339-344.
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15. Wang W, Wang Y, Gong F, Zhu W, Fu S. MTHFR C677T polymorphism and risk of congenital heart defects: evidence from 29 case-control and TDT studies. PLoS One. 2013;8(3):e58041.
16. Zhang R, Huo C, Wang X, Dang B, Mu Y, Wang Y. Two Common MTHFR Gene Polymorphisms (C677T and A1298C) and Fetal Congenital Heart Disease Risk: An Updated Meta-Analysis with Trial Sequential Analysis. Cell Physiol Biochem. 2018;45(6):2483-2496.
17. Kandaz C, Onal B, Ozen D, Demir B, Akkan AG, Ozyazgan S. Investigation of MTHFR gene C677T polymorphism in cardiac syndrome X patients. J Clin Lab Anal. 2018;32(2).
18. Muhr J, Ackerman KM. Embryology, Gastrulation. In: StatPearls. Treasure Island (FL)2021.
19. SF. G. Formation of the Neural Tube. In: Developmental Biology. 6th edition ed. Sunderland (MA): Sinauer Associates; 2000.
20. Copp AJ, Greene ND. Neural tube defects--disorders of neurulation and related embryonic processes. Wiley Interdiscip Rev Dev Biol. 2013;2(2):213-227.
21. Pitkin RM. Folate and neural tube defects. Am J Clin Nutr. 2007;85(1):285S-288S.
22. Hiraoka M, Kagawa Y. Genetic polymorphisms and folate status. Congenit Anom (Kyoto). 2017;57(5):142-149.
23. Turgal M, Gumruk F, Karaagaoglu E, Beksac MS. Methylenetetrahydrofolate Reductase Polymorphisms and Pregnancy Outcome. Geburtshilfe Frauenheilkd. 2018;78(9):871-878.
24. 24. Merviel P, Cabry R, Lourdel E, et al. Comparison of two preventive treatments for patients with recurrent miscarriages carrying a C677T methylenetetrahydrofolate reductase mutation: 5-year experience. J Int Med Res. 2017;45(6):1720-1730.