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Argument Strengthens For Folic Acid To Reduce Homocysteine Level

Increasing evidence that folic acid can dramatically curb the risk of heart disease, deep vein thrombosis, and stroke by reducing levels of homocysteine is shown in a meta analysis of some 100 studies by British investigators.

A decrease in serum homocysteine of 3 micromol/l, which can be achieved by a daily intake of about 0.8 mg folic acid, should reduce the risk of ischaemic heart disease by 16 percent, deep vein thrombosis by 25 percent, and stroke by 24 percent, declares Dr David Wald and colleagues at the Department of Cardiology, Southampton General Hospital, Southampton.

Moderate increases in serum homocysteine results from a mutation in the gene coding for the enzyme methylenetetrahydro­ folate reductase (MTHFR) in which cytosine is replaced by thymidine, the researchers point out. As the increase in homocysteine is relatively small, studies comparing the risk of cardiovascular disease in people with and without the mutation, need large numbers to show any effect, and previous meta­analyses have had too few studies available to do this.

The researchers analyzed 72 studies in which the prevalence of a mutation in the MTHFR gene was determined in 16,849 cases and controls, and 20 prospective studies among 3,820 patients of serum homocysteine and disease risk. They estimated the odds ratios of ischaemic heart disease, deep vein thrombosis and pulmonary embolism for a 5 micromol/l increase in serum homocysteine concentration.

The genetic studies and the prospective studies did not share the same potential sources of error, but both yielded similar results - strong evidence that there is a causal association between homocysteine and cardiovascular disease. The odds ratios for a 5 micromol/l increase in serum homocysteine were for ischaemic heart disease 1.42 in the genetic studies, and 1.32 in the prospective studies; for deep vein thrombosis, with or without pulmonary embolism, 1.60 in the genetic studies (there were no prospective studies); and for stroke, 1.65 in the genetic studies and 1.59 in the prospective studies.

Dr Wald and colleagues note that folic acid tablets can be taken by high risk patients with existing cardiovascular disease, or by anyone over 55. Folic acid could be supplied to the general public through food fortification, which is now done in the United States to prevent spina bifida.

"Our results strengthen the evidence that a raised serum homocysteine concentration is a cause of cardiovascular disease," they conclude.
BMJ 2002;325:1202-6.

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