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Editor—Hung et al conclude that their cohort study on serum folate and coronary heart disease provides evidence against the view that folic acid prevents coronary heart disease.1 We disagree and believe they have misinterpreted their results.
A meta-analysis of studies on homocysteine and cardiovascular disease, supported by others,2–4 together with randomised trial evidence on folic acid dose and serum homocysteine reduction, shows that the maximal homocysteine lowering effect of folic acid occurs at a dose of about 0.8 mg/day (which increases serum folate by 20 μg/l).5 This homocysteine reduction lowers the risk of coronary heart disease by about 16%. The difference in average serum folate between the highest and the lowest folate group in the cohort study of Hung et al was about 7 μg/l, since the median of the highest folate group was about 8 μg/l (the 93rd centile was stated as 9 μg/l, so the 85th centile must have been less than this) and the median in the lowest folate group was about 1 μg/l (stated as <3 μg/l).
Since a 20 mg/l higher serum folate is associated with a 16% higher risk of coronary heart disease the 7 μg/l difference will be associated with a 5% higher risk, a relative risk of 1.05 (1.167/20) consistent with the 1.10 (men) and 1.14 (women) in their study. These results weigh in favour, not against, the view that folic acid reduces the risk of coronary heart disease. The narrow range of serum folate values in their cohort study limits its ability to show a significant effect.
Table 4 in the paper confirms the link between low serum folate and increased risk of coronary heart disease. Hung et al present data from six other cohort studies. Each shows a higher risk of coronary heart disease in the lowest folate group compared with the highest. This observation alone is highly significant. The probability that all seven studies have estimates above 1.0 by chance alone is ()7 or 1 in 128, a P value of 0.008. Their negative conclusion is inappropriate.
Footnotes
Competing interests: None declared.
References
1.Hung J, Beilby JP, Knuiman MW, Divitini M. Folate and vitamin B-12 and risk of fatal cardiovascular disease: cohort study from Busselton, Western Australia. BMJ. 2003;326:131–136. doi: 10.1136/bmj.326.7381.131. . (18 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202–1208. doi: 10.1136/bmj.325.7374.1202. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Homocysteine Studies Collaboration. Homocysteine and risk of ischaemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015–2022. doi: 10.1001/jama.288.16.2015. [DOI] [PubMed] [Google Scholar]
4.Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, et al. MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023–2031. doi: 10.1001/jama.288.16.2023. [DOI] [PubMed] [Google Scholar]
5.Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D, et al. Randomised trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161:695–700. doi: 10.1001/archinte.161.5.695. [DOI] [PubMed] [Google Scholar]
Editor—Wald et al oversimplify the relation between serum folate concentration and coronary heart disease, and they have ignored our results for red cell folate, a more reliable indicator of long term folate intake than serum folate. The reference interval for red cell folate in our cohort was 114-608 μg/l in men and 101-604 μg/l in women, indicating a wide range of folate values consonant to that reported in other general populations. The power of our study to detect a relative risk of 1.2 associated with a change of one standard deviation (130 μg/l for red cell folate) was about 90% for death from cardiovascular disease and 70% for death from coronary heart disease.
Wald et al state that serum folate needs to increase by 20 μg/l to lower the risk of coronary heart disease by 16% on the premise of lowering homocysteine concentrations by 3 μmol/l.1-1 However, the Framingham heart study showed a difference >5 μmol/l in mean homocysteine concentrations across the population within a comparatively narrow range of serum folate values from 2 to 8 μg/l.1-2 We found similar results in a general population.1-3
Furthermore, the effect of raising folate concentration can be underestimated by the reduction in mean homocysteine concentration. For example, a population increase in serum folate from 4.6 to 10.0 μg/l decreased the prevalence of high homocysteine (>13 μmol/l) from 18.7% to 9.8% but reduced mean homocysteine concentration by only 0.7 μmol/l.1-4
Folates should not be assumed to prevent coronary heart disease only through lowering homocysteine concentration as other mechanisms may exist.1-5 Hence we did not argue against public health efforts to raise folate consumption in the general population by appropriate dietary measures. We argued against the routine use of vitamin supplements to lower homocysteine concentrations in the general population until their benefit is proved by controlled clinical trials.
Footnotes
Competing interests: None declared.
References
1-1.Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202–1208. doi: 10.1136/bmj.325.7374.1202. [DOI] [PMC free article] [PubMed] [Google Scholar]
1-2.Tucker KL, Mahnken B, Wilson PWF, Jacques P, Selhub J. Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA. 1996;276:1879–1885. doi: 10.1001/jama.1996.03540230029031. [DOI] [PubMed] [Google Scholar]
1-3.McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth carotid ultrasound disease assessment study (CUDAS) Circulation. 1999;99:2383–2388. doi: 10.1161/01.cir.99.18.2383. [DOI] [PubMed] [Google Scholar]
1-4.Jacques P, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340:1449–1454. doi: 10.1056/NEJM199905133401901. [DOI] [PubMed] [Google Scholar]
1-5.Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002;22:6–13. doi: 10.1161/hq0102.102190. [DOI] [PubMed] [Google Scholar]
)7 or 1 in 128, a P value of 0.008. Their negative conclusion is inappropriate.