Does an MTHFR Mutation Increase the Risk of a Stroke?

Does an MTHFR Mutation Increase the Risk of a Stroke?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

June 02, 2025

Does an MTHFR Mutation Increase the Risk of a Stroke?

Around 30-40 percent of the global population1 is affected by some form of mutation on the gene that produces the enzyme Methylenetetrahydrofolate reductase (MTHFR). Depending on the variant, the MTHFR mutation affects the body’s ability to carry out processes related to methylation.


MTHFR is required for metabolizing the amino acid homocysteine, a type of amino acid produced naturally in the body. High blood levels of homocysteine signal a breakdown in the metabolism process of this amino acid, which can have serious biochemical and life consequences.


Accumulation of homocysteine can cause irritation and inflammation of the blood vessels, increase the risk of atherosclerosis2 (hardening of the arteries), heart attack and/or stroke, and venous thrombosis (blood clots in the veins).


This article will discuss the factors associated with different MTHFR mutations and how they may increase the risk of a stroke. We will also discuss the signs to be aware of and steps you can take to reduce the risk of stroke or other cardiovascular events.

How Could an MTHFR Gene Mutation Increase the Risk of a Stroke?

Homocysteine is a type of sulfur-containing amino acid produced by the demethylation of methionine; an amino acid derived primarily from animal protein.


The body manages homocysteine levels by converting homocysteine into other products via the methionine-homocysteine pathway.3 This process requires cofactors folate, B6, and B12.


Slight deficiencies of these vitamins can lead to an accumulation in homocysteine levels. These deficiencies may occur due to poor diet and/or genetic polymorphisms4 in the key enzymes of homocysteine metabolism.


Hyperhomocysteinemia is a major risk factor in cardiovascular diseases, including cerebral stroke. Excess homocysteine damages endothelial cells and can lead to abnormal clotting, increasing the risk of stroke, especially among those with high blood pressure.5 Patients with coronary heart disease (CHD) are shown to have significantly higher mean homocysteine level6 than healthy people.


The MTHFR enzyme is a key enzyme in the folate and homocysteine metabolism,7 which means homocysteine levels are largely affected by MTHFR polymorphisms8 and folate status. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-Me-THF, which provides the methyl group for the remethylation of homocysteine to methionine, during which tetrahydrofolate (THF) is formed. Vitamin B6 and B12 act as cofactors9 in the re-methylation process, along with several other enzymes. Homocysteine levels increase as vitamin B concentrations decrease.


Folate insufficiency10 decreases the ability to re-methylate homocysteine, leading to an increased homocysteine level. Homocysteine levels may also rise when B12 is deficient, as B12 is an essential cofactor in the re-methylation cycle.


The MTHFR 677TT genotype (a double mutation), in particular, is known to decrease the availability of folate for methylation. A meta-analysis of 72 studies11 involving 12,390 cases and 16,274 controls revealed that an MTHFR C677T mutation increased the risk of ischemic stroke by around 32% compared to controls.


Similarly, the MTHFR A1298C polymorphism was shown in a meta-analysis of 40 articles,12 including 5,725 cases, to increase susceptibility to ischemic stroke in adults.

What Signs Should You Watch For?

A stroke occurs when a blood vessel that delivers oxygen to the brain either ruptures causing a bleed (hemorrhagic) or is blocked by a clot (ischemic). Brain cells served by this particular blood vessel shut down due to lack of oxygen, resulting in loss of function to the part of the body controlled by these brain cells.


Early warning signs of a stroke13 include sudden weakness, numbness and signs of paralysis, difficulty speaking, distorted vision, dizziness, difficulty walking, severe headache, possible nausea or vomiting. Stroke symptoms usually affect only one side of the body, resulting in loss of function of one arm or leg.

Can You Reduce the Risk?

Numerous studies have shown that homocysteine levels may be modified14 by providing the nutritional cofactors required for methylation and the proper functioning of the methionine cycle. This can help to reduce the risk of stroke.


Methylfolate is key to reducing homocysteine levels, especially when combined with vitamins B12 and B6.


An analysis of 12 trials including 1,114 subjects15 found that folic acid supplementation resulted in a decrease in serum homocysteine levels, with an overall reduction of 25% decrease in homocysteine. Combined vitamin B12 supplementation produced a modest additional 7% reduction in homocysteine levels.


Similarly, a 2019 systematic review of intake of vitamin B6, folate, and vitamin B12 and the risk of coronary heart disease found that a higher intake16 of folate and vitamin B6 was associated with a lower risk of coronary heart disease in the general population.


Also worth noting is a study involving 12,000 Indian soldiers working in a high-altitude environment, which showed that daily supplementation with folate, vitamin B6, and vitamin B12 reduced thrombotic events17 over a period of 2 years.

Can Supplementation Help Reduce the Risk for People with MTHFR?

The above studies have shown that the effects of an MTHFR variant on homocysteine can be modified by improving the concentration of folate18 in the body. However, this should not be confused with folic acid.


Folic acid is not recommended19 for those with MTHFR polymorphisms. It is not the bioequivalent of natural dietary folates and cannot cross the blood-brain barrier. It has no coenzyme activity and must be reduced to tetrahydrofolate form (the metabolically active form) before being used by the body. Folic acid has not been shown to lower homocysteine directly20 and may cause renal toxicity.


Methylfolate (L-5-methyl-THF) is considered superior to folic acid21 as it doesn’t mask the hematological symptoms of vitamin B12 deficiency, and it is less likely to interact with drugs that inhibit dihydrofolate reductase (the enzyme that converts dihydrofolate to tetrahydrofolate).


Most importantly, methylfolate can bypass folate insufficiency22 due to MTHFR deficiency. Unlike folic acid, it can enter the folate cycle directly without the need for further enzymatic modification.


Methylfolate supplements are readily available over-the-counter and online, often labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.


One brand specifically recommended for people with a heightened need for bioavailable folate is Methyl-Life®. The Methyl-Life® product range is made with the internationally-patented Magnafolate® PRO, clinically tested as the world’s purest methylfolate23 and the most active form of folate in plasma circulation.24 Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body.


The Methyl-Life® range includes methylfolate dosages from 2.5mg to 15mg, Active B12, and Methylated Multivitamins.

References

  1. Traci Stein; "A Genetic Mutation That Can Affect Mental & Physical Health"; Psychology Today; 2014 Sep

    https://www.psychologytoday.com/us/blog/the-integrationist/201409/genetic-mutation-can-affect-mental-physical-health

  2. Paul Ganguly, Sreyoshi Fatima Alam; "Role of homocysteine in the development of cardiovascular disease"; Nutrition journal; 2015 Jan

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326479/

  3. Avinash Kumar, Henry A. Palfrey, Rashmi Pathak, Philip J. Kadowitz, Thomas W. Gettys, Subramanyam N. Murthy; "The metabolism and significance of homocysteine in nutrition and health"; Open Access; 2017 Dec

    https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-017-0233-z

  4. Henk J Blom, Yvo Smulders; "Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects"; Journal of inherited metabolic disease; 2010 Sep

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026708/

  5. Liping Liu, David Wang, K S Lawrence Wong, Yongjun Wang; "Stroke and stroke care in China: huge burden, significant workload, and a national priority"; Stroke; 2011 Dec

    https://pubmed.ncbi.nlm.nih.gov/22052510/

  6. Paul Ganguly, Sreyoshi Fatima Alam; "Role of homocysteine in the development of cardiovascular disease"; Nutrition journal; 2015 Jan

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326479/

  7. Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak, Irena Mlinarič-Raščan; "Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate"; Journal of clinical medicine; 2020 Sep

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

  8. Min Zhao, Xiaobin Wang, Mingli He, Xianhui Qin, Genfu Tang, Yong Huo, Jianping Li, Jia Fu, Xiao Huang, Xiaoshu Cheng, Binyan Wang, Fan Fan Hou, Ningling Sun, Yefeng Cai; "Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention"; Stroke; 2017 Mar

    https://www.ahajournals.org/doi/10.1161/STROKEAHA.116.015324

  9. Henk J Blom, Yvo Smulders; "Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects"; Journal of inherited metabolic disease; 2010 Sep

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026708/

  10. Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak, Irena Mlinarič-Raščan; "Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate"; Journal of clinical medicine; 2020 Sep

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

  11. P A Abhinand, M Manikandan, R Mahalakshmi, P K Ragunath; "Meta-analysis study to evaluate the association of MTHFR C677T polymorphism with risk of ischemic stroke"; Bioinformation; 2017 Jun

    https://pubmed.ncbi.nlm.nih.gov/28729765/

  12. Xiaobo Dong, Jun Wang, Gesheng Wang, Jiayue Wang, Lei Wang, Yong Du; "MTHFR A1298C gene polymorphism on stroke risk: an updated meta-analysis"; Genes and environment; 2021 Sep

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467014/

  13. InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006

    https://www.ncbi.nlm.nih.gov/books/NBK279214/

  14. Elizabeth A. Varga, Amy C. Sturm, Caron P. Misita, Stephan Moll; "Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease"; Circulation; 2005 May

    https://www.ahajournals.org/doi/10.1161/01.cir.0000165142.37711.e7

  15. Homocysteine Lowering Trialists’ Collaboration; "Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration"; BMJ : British medical journal / British Medical Association; 1998 Mar

    https://pubmed.ncbi.nlm.nih.gov/9569395/

  16. Ahmad Jayedi, Mahdieh Sadat Zargar; "Intake of vitamin B6, folate, and vitamin B12 and risk of coronary heart disease: a systematic review and dose-response meta-analysis of prospective cohort studies"; Critical reviews in food science and nutrition; 2019

    https://pubmed.ncbi.nlm.nih.gov/30431328/

  17. Jyoti Kotwal, Atul Kotwal, Sandeep Bhalla, P K Singh, Velu Nair; "Effectiveness of homocysteine lowering vitamins in prevention of thrombotic tendency at high altitude area: A randomized field trial"; Thrombosis research; 2015 Oct

    https://pubmed.ncbi.nlm.nih.gov/26319423/

  18. Michael V Holmes, Paul Newcombe, Jaroslav A Hubacek, Reecha Sofat, Sally L Ricketts, Jackie Cooper, Monique MB Breteler, Leonelo E Bautista, Pankaj Sharma, John C Whittaker, Liam Smeeth, F Gerald R Fowkes, Ale Algra, Veronika Shmeleva, Zoltan Szolnoki, Mark Roest, Michael Linnebank, Jeppe Zacho, Michael A Nalls, Andrew B Singleton, Luigi Ferrucci, John Hardy, Bradford B Worrall, Stephen S Rich, Mar Matarin, Paul E Norman, Leon Flicker, Osvaldo P Almeida, Frank M van Bockxmeer, Hiroshi Shimokata, Kay-Tee Khaw, Nicholas J Wareham, Martin Bobak, Jonathan AC Sterne, George Davey Smith, Philippa J Talmud, Cornelia van Duijn, Steve E Humphries, Jackie F Price, Shah Ebrahim, Debbie A Lawlor, Graeme J Hankey, James F Meschia, Manjinder S Sandhu, Aroon D Hingorani, Juan P Casas; "Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials"; The Lancet; 2011 Aug

    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60872-6/fulltext

  19. Merrill F Elias, Craig J Brown; "New Evidence for Homocysteine Lowering for Management of Treatment-Resistant Hypertension"; American Journal of Hypertension; 2021 Dec

    https://academic.oup.com/ajh/advance-article/doi/10.1093/ajh/hpab194/6475983

  20. Merrill F Elias, Craig J Brown; "New Evidence for Homocysteine Lowering for Management of Treatment-Resistant Hypertension"; American Journal of Hypertension; 2021 Dec

    https://academic.oup.com/ajh/advance-article/doi/10.1093/ajh/hpab194/6475983

  21. Klaus Pietrzik, Lynn Bailey, Barry Shane; "Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics"; Clinical pharmacokinetics; 2010 Aug

    https://pubmed.ncbi.nlm.nih.gov/20608755/

  22. Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak, Irena Mlinarič-Raščan; "Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate"; Journal of clinical medicine; 2020 Sep

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

  23. Magnafolate.com; "Magnafolate® PRO"; 2021

    https://www.magnafolate.com/products/magnafolate-pro.html

  24. --

    https://i.trade-cloud.com.cn/upload/6405/file/20210929/english-version-magnafolate-enhancing-immunity_524485.pdf

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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