(02-11-11) Diet, Genes, and Stroke Risk: Another Look at Homocysteine and Folate

A genetic analysis and a meta-analysis suggest that lowering homocysteine levels reduces stroke risk more in low-folate regions than in areas with folate fortification, and that folate status modifies the effect of MTHFR alleles on stroke risk.
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.
Comment: These findings suggest that homocysteine-lowering therapy would have the greatest effect in geographic areas with low dietary folate consumption. Because RCTs have failed to show benefit of folate therapy (Arch Intern Med 2010; 170:1622) and have suggested that there may even be harm (N Engl J Med 2006; 354:1578), I would not currently recommend folate supplementation. However, folate supplementation may have a role in those with the MTHFR 677C T variant, particularly in low-folate regions. To date, no trial has been conducted exclusively in a low-folate region to evaluate the effect of homocysteine reduction on stroke risk. The ongoing China Stroke Primary Prevention Trial ? which is comparing stroke risk with enalapril alone to enalapril plus folic acid in hypertensive individuals without established cardiovascular disease ? may show whether homocysteine lowering can reduce stroke risk in low-folate regions.
? Amytis Towfighi, MD
Source: Dr. Towfighi is Assistant Professor, Department of Neurology, University of Southern California, Los Angeles; and Chair, Department of Neurology, Rancho Los Amigos National Rehabilitation Center, Downey, CA.
Published in Journal Watch Neurology October 25, 2011

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