What is the significance of the Methylenetetrahydrofolate Reductase (MTHFR) gene?

From the Guidelines

The MTHFR gene variant is not a significant predictor of stroke risk, and routine genetic testing is not recommended for the general population. The relationship between MTHFR gene variants and stroke risk is complex, and current evidence suggests that the association is weaker than previously thought 1. While some studies have found an increased risk of stroke associated with the MTHFR C677T genotype, others have found no significant association 1.

Key Findings

• The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase, which plays a key role in processing amino acids and converting folate (vitamin B9) into its active form.
• Variations in this gene, particularly the C677T and A1298C polymorphisms, are relatively common in the population and may reduce the enzyme's efficiency, potentially affecting folate metabolism and homocysteine levels in the body.
• Current medical evidence does not support routine genetic testing for MTHFR in the general population, and most people with MTHFR variants do not require special treatment beyond standard nutritional recommendations.

Recommendations

• Maintaining a balanced diet rich in folate (leafy greens, legumes, fruits) and other B vitamins is beneficial regardless of genetic status.
• Decisions about supplementation should be made in consultation with healthcare providers based on individual health needs rather than genetic status alone.
• The significance of MTHFR variants has been overstated in some alternative health circles, and a careful evaluation of the evidence is necessary to make informed decisions about testing and treatment.

Evidence-Based Practice

• A meta-analysis of 10 randomized trials of folic acid found that treatment decreased carotid intima-media thickness (IMT) but with substantial heterogeneity resulting from larger effects at higher baseline IMTs or with greater reductions in homocysteine 1.
• The VITATOPS trial found no effect of B vitamin supplementation on risk of stroke, but a post hoc analysis suggested a potential benefit in patients not taking antiplatelet medication 1.
• A meta-analysis of folic acid supplementation in 26 randomized, controlled trials found no effect on the risk of cardiovascular disease but a trend toward reduced stroke risk 1.

From the Research

MTHFR Gene and Folate Status

• The MTHFR gene plays a crucial role in folate metabolism, with the T variant increasing the risk of low folate status, particularly when combined with low folate intake 2.
• Individuals with the MTHFR 677TT genotype have higher plasma homocysteine levels and lower serum folate levels compared to those with the CT or CC genotypes 2, 3, 4.
• Folate deficiency has the greatest contribution to elevated serum homocysteine levels, followed by the MTHFR C677T polymorphism and vitamin B12 deficiency 4.

MTHFR Gene and Homocysteine Levels

• The MTHFR genotype is a strong determinant of plasma homocysteine levels, with the TT genotype associated with higher homocysteine levels 3, 4.
• A significant negative correlation exists between serum homocysteine levels and folate and vitamin B12 levels 3, 4.
• Supplementation with folic acid, vitamins B6 and B12 can lower homocysteine concentrations in patients with MTHFR mutations and hyperhomocysteinemia 5, 6.

MTHFR Gene and Disease Risk

• The MTHFR genotype does not increase the risk for premature coronary artery disease 3.
• However, hyperhomocysteinemia is associated with an increased risk of chronic allograft dysfunction in renal transplant recipients 6.
• Supplementation with folic acid, vitamins B6 and B12 may contribute to reducing the risk of disease associated with hyperhomocysteinemia, particularly in individuals with MTHFR mutations 5, 6.