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 US, while around 322,000 have definite or probable SLE. 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.

Lupus is a chronic inflammatory autoimmune disease 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 autoantibodies and immune complexes, leading to eventual organ damage. The skin, musculoskeletal system, and pulmonary system are primarily affected.

Typical signs and symptoms 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). 

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 lupus 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 677TT mutation compared to both Rheumatoid Arthritis (RA) patients and healthy controls. 

One study showed that 25% of patients with SLE 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-analysis 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.

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

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

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

A 2021 study found similar results, with SLE patients showing higher homocysteine levels 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.

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-12, 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 acid 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.