The Relationship Between an MTHFR Gene Mutation and Lupus

The Relationship Between an MTHFR Gene Mutation and Lupus

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 28, 2025

Table of Contents

    The Relationship Between an MTHFR Gene Mutation and Lupus

    Lupus is an autoimmune disease without a known cure. An estimated five million people worldwide have some form of lupus, but most are affected by systemic lupus erythematosus (SLE), which will be the main focus of this article.


    SLE is diagnosed in around 161,000 people in the US1, while around 322,000 have definite or probable SLE2. It is most often seen in women of child-bearing age and is even more common in African-Americans, Asians, Hispanics, and Native Americans.


    The pathophysiological understanding of lupus is constantly evolving. Recent research has identified several internal and external factors that may contribute to its onset, including hormones, genetics, and the environment. Among these is a possible link to functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR), which may explain the high prevalence of elevated homocysteine levels among people living with lupus.


    This article will explain lupus and discuss how it may be linked to an MTHFR genetic mutation and what treatment options may be available.

    What Exactly is Lupus?

    Lupus is a chronic inflammatory autoimmune disease3 that affects multiple organ systems of the body. There are four main types of lupus: neonatal, discoid, drug-induced, and systemic lupus erythematosus (SLE), which is the most common.


    Lupus results in abnormal immunological function and the production of autoantibodies, leading to immune complexes that may destroy healthy tissue. Symptoms may range from none at all to periodic flares of varying severity.


    SLE causes the formation and deposition of autoantibodies4 and immune complexes, leading to eventual organ damage. The skin, musculoskeletal system, and pulmonary system are primarily affected.


    Typical signs and symptoms5 of SLE include fever, fatigue, arthralgia  and weight loss. However, every patient may experience symptoms differently.


    The most common sign is a red “butterfly” malar rash on the nose and cheeks following exposure to the sun. Other symptoms include skin conditions such as alopecia, Reynaud’s phenomenon, and sores in the mouth or nose.


    The musculoskeletal system is also affected, leading to joint pain and stiffness, muscle pain, and/or arthritis. Arthritis can affect minor or major joints, causing occasional or persistent inflammation.


    Patients with pulmonary symptoms may experience painful breathing, coughing, and shortness of breath. SLE also affects the cardiovascular, gastrointestinal, renal, and hematological systems and the central nervous system (CNS). 

    Can an MTHFR Gene Mutation Cause Lupus?

    Research is ongoing as to whether MTHFR mutations could cause lupus, and scientists have stated that more studies are needed to reach a consensus. That said, MTHFR mutations may worsen the effects of lupus.


    Numerous studies have identified MTHFR genetic mutations as major contributors to elevated homocysteine levels, along with deficiencies in folate, vitamin B6, or vitamin B12.


    Increased homocysteine levels are seen in approximately 15% of patients with lupus6 and are associated with an increased risk of atherothrombotic events in these patients.


    Patients with lupus are found to have a significantly higher prevalence of the MTHFR homozygous 677TT7 mutation compared to both Rheumatoid Arthritis (RA) patients and healthy controls.


    One study showed that 25% of patients with SLE8 had a TT double mutation on the 677 allele of the MTHFR gene while 10.5% had CC double mutations on the 1298 allele.


    A meta-analysis9 of seven eligible studies involving 882 cases found that the MTHFR C677T (rs1801133) contributed to the susceptibility of SLE. However, the researchers pointed out that more case-control studies and larger sample sizes should be conducted to validate these findings.

    Is Lupus Worse for Someone with MTHFR?

    Every patient with lupus is affected differently. However, having both the symptoms of lupus and MTHFR may reduce the overall quality of life, particularly in the case of B12 deficiency and elevated homocysteine levels.


    Hyperhomocysteinemia and cardiovascular disease10 are prevalent in both lupus patients and those with MTHFR  mutations. Accelerated atherosclerosis (hardening of the arteries) is more common in women with SLE11 compared to the general population.


    Those with lupus may develop antibodies to intrinsic factor12, reducing B12 absorption.


    One study found that 46% of patients with SLE also have anemia13, and 24% had low levels of B12.


    A 2021 study found similar results, with SLE patients showing higher homocysteine levels14 and lower vitamin B12 levels than those without SLE.


    B12 deficiency can increase the risk of symptoms associated with MTHFR mutations, such as elevated homocysteine, depression and anxiety, chronic pain and fatigue, nerve pain, and migraines.

    Are There Treatment Options?

    SLE is a chronic disease requiring long-term management. Lowering homocysteine concentrations is key to slowing the development and progression of further health issues.


    Sufficient vitamin B12 is key to managing healthy homocysteine levels. Supplementation of folic acid, vitamin B-1215, pyridoxine, betaine, dimethylglycine (DMG), and choline is also known to lower elevated homocysteine levels in most patients with the MTHFR genetic defect.


    Treatment with a combination of vitamin B and folic acid16 has been recommended for patients with lupus nephritis. That said, folic acid may not be the best option for those with MTHFR as it has been shown to have numerous drawbacks when compared to methylfolate supplementation.

    How Could Supplements Help?

    Low levels of vitamin B12 can be corrected with supplementation. B12 works alongside folate and vitamin B6 to reduce homocysteine. When taken alongside folate, B12 helps to lower homocysteine levels more effectively than taking folate alone.


    Many commercial supplements contain the cyanocobalamin form of B12 that the body cannot use effectively, particularly when absorption is compromised.


    The most bioavailable forms of B12 include17Hydroxocobalamin (OHCbl), Adenosylcobalamin (AdCbl), and Methylcobalamin (MeCbl). These forms are bioidentical to those naturally occurring in your body and can be used immediately.


    Methyl-Life’s® B12 Complete is a proprietary formula that contains all three active forms of B12. It’s suitable for vegans, vegetarians, and those who have B12 deficiencies, Parkinson’s, Crohn’s, mental health issues, or people with MTR, MTRR, COMT, or other gene defects affecting B12 metabolism.

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    References

    1. Charles G Helmick, David T Felson, Reva C Lawrence, Sherine Gabriel, Rosemarie Hirsch, C Kent Kwoh, Matthew H Liang, Hilal Maradit Kremers, Maureen D Mayes, Peter A Merkel, Stanley R Pillemer, John D Reveille, John H Stone, National Arthritis Data Workgroup; "Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I"; Arthritis and rheumatism.; 2008 Jan

      https://pubmed.ncbi.nlm.nih.gov/18163481/

    2. Charles G Helmick, David T Felson, Reva C Lawrence, Sherine Gabriel, Rosemarie Hirsch, C Kent Kwoh, Matthew H Liang, Hilal Maradit Kremers, Maureen D Mayes, Peter A Merkel, Stanley R Pillemer, John D Reveille, John H Stone, National Arthritis Data Workgroup; "Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I"; Arthritis and rheumatism.; 2008 Jan

      https://pubmed.ncbi.nlm.nih.gov/18163481/

    3. William Maidhof, Olga Hilas; "Lupus: An Overview of the Disease And Management Options"; P & T : a peer-reviewed journal for formulary management; 2012 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351863/

    4. C C Mok, C S Lau; "Pathogenesis of systemic lupus erythematosus"; Journal of clinical pathology; 2003 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769989/

    5. Manole COJOCARU, Inimioara Mihaela COJOCARU, Isabela SILOSI, Camelia Doina VRABIE; "Manifestations of Systemic Lupus Erythematosus"; Mædica; 2011 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391953/

    6. Homa Timlin, Rebecca Manno, Homeyra Douglas; "Hyperhomocysteinemia and Lupus Nephritis"; Cureus; 2019 Jul

      https://www.cureus.com/articles/21199-hyperhomocysteinemia-and-lupus-nephritis

    7. Maira Giannelou, Andrianos Nezos, Sofia Fragkioudaki, Dimitra Kasara, Kyriaki Maselou, Nikolaos Drakoulis, Dimitris Ioakeimidis, Haralampos M Moutsopoulos, Clio P Mavragani; "Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis"; Clinical immunology : the official journal of the Clinical Immunology Society; 2018 Aug

      https://pubmed.ncbi.nlm.nih.gov/29501539/

    8. Clio P. Mavragani, Maira Giannelou, Ioanna Papadaki, Eleni Antypa, Dimitrios Ioakeimidis, Haralampos M. Moutsopoulos, Michael Koutsilieris, Department of Experimental Physiology, School of Medicine, University of Athens, Athens, Greece, Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece, Department of Rheumatology, General Hospital of Athens "G.Gennimatas", Athens, Greece, Department of Radiology, General Hospital of Athens, Greece, Department of Rheumatology, General Hospital, Greece, Department of Physiology, Athens University Medical School, Athens, Greece; "MTHFR Polymorphisms in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Associations with Intima Media Thickness Scores"; American College of Rheumatology; 2012

      https://acrabstracts.org/abstract/mthfr-polymorphisms-in-systemic-lupus-erythematosus-and-rheumatoid-arthritis-associations-with-intima-media-thickness-scores/

    9. Huang-yan Zhou, Min Yuan; "MTHFR polymorphisms (rs1801133) and systemic lupus erythematosus risk"; Medicine; 2020 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535654/

    10. Homa Timlin, Rebecca Manno, Homeyra Douglas; "Hyperhomocysteinemia and Lupus Nephritis"; Cureus; 2019 Jul

      https://www.cureus.com/articles/21199-hyperhomocysteinemia-and-lupus-nephritis

    11. Homa Timlin, Rebecca Manno, Homeyra Douglas; "Hyperhomocysteinemia and Lupus Nephritis"; Cureus; 2019 Jul

      https://www.cureus.com/articles/21199-hyperhomocysteinemia-and-lupus-nephritis

    12. Caroline Gordon; "Constitutional Features of Systemic Lupus Erythematosus"; Musculoskeletal Key; 2018 Jul

      https://musculoskeletalkey.com/constitutional-features-of-systemic-lupus-erythematosus/#bib1

    13. Refael Segal, Yehuda Baumoehl, Ori Elkayam, David Levartovsky, Irena Litinsky, Daphna Paran, Irena Wigler, Beni Habot, Arthur Leibovitz, Ben Ami Sela, Dan Caspi; "Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus"; Rheumatology international; 2004 Jan

      https://pubmed.ncbi.nlm.nih.gov/12720045/

    14. Tsung-Yu Tsai, Tsai-Hsien Lee, Hsiao-Han Wang, Ting-Hua Yang, I-Jing Chang, Yu-Chen Huang; "Serum Homocysteine, Folate, and Vitamin B12 Levels in Patients with Systemic Lupus Erythematosus: A Meta-Analysis and Meta-Regression"; Journal of the American College of Nutrition; 2021 Jul

      https://pubmed.ncbi.nlm.nih.gov/32702250/

    15. The Journal of Nutrition | A Journal of the American Society for Nutrition

      https://academic.oup.com/jn/article/126/suppl_4/1273S/4724802?login=false

    16. Homa Timlin, Rebecca Manno, Homeyra Douglas; "Hyperhomocysteinemia and Lupus Nephritis"; Cureus; 2019 Jul

      https://www.cureus.com/articles/21199-hyperhomocysteinemia-and-lupus-nephritis

    17. Cristiana Paul, David M Brady; "Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms"; Integrative medicine; 2017 Feb

      https://pubmed.ncbi.nlm.nih.gov/28223907/

    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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