(Circulation. 1998;98:2520-2526.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease
The Result of a Meta-Analysis
From the Departments of Medicine (L. Brattström) and Clinical Physiology (L. Brudin), County Hospital, Kalmar, Sweden; Department of Cardiovascular Medicine (D.E.L.W.), University of New South Wales, The Prince Henry and Prince of Wales Hospitals, Sydney, Australia; and Department of Statistics (J.Ö.), The Swedish University of Agricultural Sciences, Uppsala, Sweden.
Correspondence to Assoc Prof Lars Brattström, Department of Medicine, Kalmar Hospital, S-391 85 Kalmar, Sweden. E-mail lars.brattstrom{at}alinks.se
Background—The results of
retrospective and prospective case-control studies have clearly
established that mild elevations of the plasma homocysteine level are
associated with increased risk of coronary, cerebral, and
peripheral vascular disease. Recently, a mutation
(677C
T) was identified in the
methylenetetrahydrofolate reductase
(MTHFR) gene that results in reduced folate-dependent enzyme activity
and reduced remethylation of homocysteine to methionine. Mutant
homozygotes (TT genotype) constitute 
12% of the white
population and frequently have mildly elevated circulating
homocysteine. Therefore, it seems likely that they would also be at
increased risk of vascular disease. A number of studies have
investigated this during the past 3 years, and the present article
evaluates the results in a meta-analysis.
Methods and Results—We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 µmol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37).
Conclusions—We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.
Key Words: homocysteine • methylenetetrahydrofolate reductase • risk factors • coronary disease
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