(Circulation. 1997;96:2573-2577.)
© 1997 American Heart Association, Inc.
Articles |
Thermolabile Methylenetetrahydrofolate Reductase in Coronary Artery Disease
From the Departments of Pediatrics (L.A.J.K., S.G.H., L.P.W.J. van den H., F.J.M.T., H.J.B.), Internal Medicine (G.H.J.B.), and Cardiology (F.W.A.V., F.W.), University Hospital Nijmegen; the Department of Hematology, Academical Medical Center, Amsterdam (J.J.P.K.); the Department of Clinical Chemistry, University Hospital Rotterdam (J.L., G.J.M.B.); and the Department of Cardiology, University Hospital Leiden (A.V.G.B., J.W.J.), The Netherlands.
Correspondence to Dr H.J. Blom, Department of Pediatrics, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail H.Blom{at}ckslkn.azn.nl
Background Hyperhomocysteinemia, an independent and graded
risk factor for coronary artery disease (CAD), may result from
both environmental and hereditary factors.
Methylenetetrahydrofolate reductase
(MTHFR) catalyzes the conversion of
methylenetetrahydrofolate to
methyltetrahydrofolate, the methyl donor in the remethylation of
homocysteine to methionine. A 677C
T mutation in the MTHFR gene has
been associated with elevated homocysteine concentrations in homozygous
(+/+) individuals.
Methods and Results We assessed the frequency of this common mutation in 735 CAD patients from the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering coronary-regression trial, and in 1250 population-based control subjects. Furthermore, the association between the mutation and serum homocysteine concentrations was studied. The frequency of the homozygous (+/+) mutation was 9.5% among patients versus 8.5% among control subjects, resulting in an odds ratio of 1.21 (95% confidence interval [CI], 0.87 to 1.68), relative to the (-/-) genotype. Homocysteine concentrations were significantly elevated in both (+/+) and (+/-) individuals compared with (-/-) individuals (median homocysteine levels, 15.4, 13.4, and 12.6 µmol/L, for (+/+), (+/-), and (-/-) individuals, respectively). For a summary estimation of the risk of the (+/+) genotype for CAD, we performed a meta-analysis on 8 different case-control studies on thermolabile MTHFR in CAD. In the meta-analysis, the homozygous (+/+) genotype was present in 299 of 2476 patients (12.1%) and in 257 (10.4%) of 2481 control subjects, resulting in a significant odds ratio of 1.22 (95% CI, 1.01 to 1.47) relative to the (-/-) genotype.
Conclusions Both the homozygous (+/+) and heterozygous (+/-) genotype result in elevated homocysteine concentrations. From our meta-analysis, we conclude that the homozygous (+/+) genotype is a modest but significant risk factor for CAD.
Key Words: homocysteine • methylenetetrahydrofolate reductase • coronary disease • meta-analysis • risk factors
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
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|
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|
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|
|
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|
|
|
|
 |
|
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|
|
|
 |
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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