Diet, Genes, and Stroke Risk: Another Look at Homocysteine and Folate

The MTHFR 677C→T polymorphism is associated with elevated homocysteine levels and with increased stroke risk. Vitamin therapy with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels; however, randomized controlled trials (RCTs) of vitamin therapy for elevated homocysteine levels have not shown reductions in stroke risk (Arch Intern Med 2010; 170:1622). Folate consumption affects serum homocysteine levels and varies by geographic region. The RCTs evaluating the effect of homocysteine lowering on stroke risk were predominantly performed in areas with folic acid supplementation, which could explain the lack of benefit.

To investigate the potential modifying effect of folate status on the association between the MTHFR 677C→T variant and stroke risk, researchers reassessed genetic studies that included data for homocysteine concentration and stroke. The investigators compared their genetic-analysis findings with a meta-analysis of 13 RCTs of homocysteine-lowering treatments to reduce stroke risk and found the following:

• The effect of the MTHFR 677C→T polymorphism on homocysteine concentration was modified substantially by folate consumption: The effect was larger in low-folate areas (e.g., Asia) than in areas with folate fortification (e.g., the U.S.).

• The effect of the MTHFR 677C→T polymorphism on stroke risk was also larger in low-folate regions than in areas with folate fortification.

• In an analysis limited to only large studies, the authors predicted that lowering homocysteine levels would reduce stroke risk more in low-folate regions than in areas with folate fortification.