MTHFR allele and homocysteine

• evidence suggests that moderately elevated homocysteine plasma levels (moderate hyperhomocysteinaemia) are common in the general population - reflects less critical defects in methionine metabolism and a deficiency in nutritional factors (folic acid, B12 and possible B6)
• there is now evidence that moderate hyperhomocysteinaemia is associated with an increased risk of vascular events including stroke, coronary heart disease and venous thrombosis - it may however be that raised homocysteine levels are just a marker of established risk and an atherogenic diet (i.e. deficient in fruit and vegetables, and B vitamins)
• folate supplementation lowers homocysteine levels
• randomised controlled trials of folate supplementation in the primary and secondary prevention of vascular disease will establish the causal role (or not) of raised homocysteine concentrations
  • there is evidence that in patients having percutaneous coronary intervention, homocysteine lowering treatment with folic acid, vitamin B12, and vitamin B6 reduced the need for repeated revascularisation and adverse coronary outcomes (3)
  • however the evidence from more recent trials is disappointing
    • in the Heart Outcomes Prevention Evaluation (HOPE) 2 trial (4) supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease
    • the NORVIT trial investigated the use of folic acid plus vitamins B12 or vitamin B6 following myocardial infarction and found that treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. The authors noted that a harmful effect from combined B vitamin treatment was suggested and such treatment should therefore not be recommended (5)
    • the Vitamin Intervention for Stroke Prevention trial shows that in 3,680 patients with stroke, two years of treatment with vitamins lowers homocysteine levels significantly but does not reduce the rate of future vascular events (6)
• a review suggests that there is "...a consensus emerging that the hypothesis that homocysteine lowering with vitamins can reduce future cardiovascular events is incorrect. If we must accept that the epidemiologically reproducible relationship between homocysteine and vascular disease is genuine, as it appears to be, then it is potentially far more complex than previously believed and will require further thought. Clinically, there is now little justification for using folic acid or B vitamins in patients with established cardiovascular disease, whether or not they have elevated homocysteine levels...(7)"
• in terms of primary prevention of stroke (8,9):
  • a meta-analysis concluded that "our findings indicate that folic acid supplementation can effectively reduce the risk of stroke in primary prevention" (8)
  • HOPE 2 investigators have analyzed stroke outcomes among participants of the HOPE 2 trial that randomized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or matching placebo, for 5 years
    • the incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group - the hazard ratio [HR], 0.75; 95% (CI, 0.59-0.97) was significant
    • vitamin therapy also significantly reduced the risk of nonfatal stroke (HR, 0.72; 95% CI, 0.54-0.95) but did not impact on neurological deficit at 24 hours (P=0.45) or functional dependence at discharge or at 7 days (OR, 0.95; 95% CI, 0.57-1.56)
    • this study data suggests that homocysteine lowering therapy may have a role in lowering stroke risk (9)

Notes:

• homocysteine levels and stroke:
  • individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype
  • there is epidemiological evidence (10) that the observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke

References:

1. British Heart Foundation, Factfile 3/2000.
2. Ann Intern Med 1999;131:363-75.
3. Schnyder G et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B12 and vitamin B6 on clinical outcome after percutaneous coronary interventions: the Swiss Heart study: a randomized controlled trial. JAMA (2002), 288, 937-9
4. Lonn E et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77.
5. Bonaa KH et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006 Apr 13;354(15):1578-88
6. Toole JF et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.
7. BJC 2007;14(2):69-70.
8. Wang X et al.Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.Lancet. 2007 ;369:1876-82.
9. Saposnik G et al.; Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trialStroke. 2009 Apr;40(4):1365-72.
10. Casas JP et al. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 2005;365:224-32