Abstract
BackgroundResults from genetic epidemiological studies suggest that raised serum homocysteine is a cause of ischaemic heart disease, but the results of randomised trials suggest otherwise. We aimed to update meta-analyses on each type of study using the latest published data and test a hypothesis based on antiplatelet therapy use in the trials to explain the discrepancy.Methods and FindingsMeta-analyses of ischaemic heart disease using (i) 75 studies in which the prevalence of a mutation (CT) in the MTHFR gene (which increases homocysteine) was determined in cases (22,068) and controls (23,618), and (ii) 14 randomised trials (39,597 participants) of homocysteine lowering and ischaemic heart disease events. The summary estimates from the two analyses were compared. Meta-analysis of the MTHFR studies showed a statistically significantly increased risk of ischaemic heart disease in TT compared with CC homozygotes; odds ratio 1.16 (1.04 to 1.29) for a 1.9 µmol/L homocysteine difference (TT minus CC). Meta-analysis of randomised trials showed no significant reduction in IHD risk from folic acid; relative risk 1.00 (0.93 to 1.08), despite a reduction in homocysteine of 3.3 µmol/L. There was a statistically significant difference in risk reduction between the 5 trials with the lowest prevalence of antiplatelet therapy (60% on average, usually aspirin), RR 0.93 (0.84 to 1.05) and the 5 trials with the highest prevalence (91% on average), RR 1.09 (1.00 to 1.19), p = 0.037 for the difference.ConclusionDiscordant results from MTHFR studies and randomised trials could be explained by aspirin reducing or negating the anti-platelet effect of lowering homocysteine. On this basis, folic acid would have a role in the primary prevention of ischaemic heart disease, when aspirin is not taken routinely, but not in secondary prevention, when it is routine.
Highlights
There is uncertainty over whether raised serum homocysteine concentrations cause ischaemic heart disease
Discordant results from methylenetetrahydrofolate reductase (MTHFR) studies and randomised trials could be explained by aspirin reducing or negating the anti-platelet effect of lowering homocysteine
Folic acid would have a role in the primary prevention of ischaemic heart disease, when aspirin is not taken routinely, but not in secondary prevention, when it is routine
Summary
There is uncertainty over whether raised serum homocysteine concentrations cause ischaemic heart disease. Two types of study provide evidence: (i) case control studies of the prevalence of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (a common genetic variant that leads to moderate increases in serum homocysteine levels) among people with and without ischaemic heart disease [1,2] and (ii) randomised trials of B vitamins, which lower serum homocysteine, in the prevention of ischaemic heart disease events.[3] The randomised trials should be a valid test of the hypothesis that homocysteine causes ischaemic heart disease, provided risk can be reversed within a few years – the duration of most of the trials. The MTHFR studies, themselves, provide evidence of causality comparable to that obtained from the randomised controlled trials, in that the serum homocysteine differences in people with and without the polymorphism occur as a result of a randomly allocated genetic mutation and the two groups would not be expected to differ in other respects. Results from genetic epidemiological studies suggest that raised serum homocysteine is a cause of ischaemic heart disease, but the results of randomised trials suggest otherwise. We aimed to update meta-analyses on each type of study using the latest published data and test a hypothesis based on antiplatelet therapy use in the trials to explain the discrepancy
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