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(Circulation. 1996;94:1812-1814.)
© 1996 American Heart Association, Inc.
Articles |
Genetic Polymorphism of Methylenetetrahydrofolate Reductase and Myocardial Infarction
A Case-Control Study
the Divisions of Cardiovascular Diseases (C.S., K.L., J.M.G.) and Preventive Medicine (J.B., J.M.G.), Department of Medicine, Brigham and Women's Hospital; the Department of Cardiology, Children's Hospital (K.L.); the Department of Ambulatory Care and Prevention (J.B.), Harvard Medical School; the Department of Nutrition (P.V.), Harvard School of Public Health, Boston, Mass; and the Department of Epidemiology and Public Health (P.V.), Agricultural University, Wageningen, Netherlands.
Correspondence to Klaus Lindpaintner, MD, Division of Cardiovascular Diseases, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail kl@calvin.bwh.harvard.edu.
Background Elevated total plasma homocyst(e)ine (tHcy; the composite of homocysteine-derived moieties in their oxidized and reduced forms) levels are a risk factor for coronary heart disease, stroke, and venous thrombosis. tHcy plasma levels are influenced by folate, vitamins B6 and B12, as well as by hereditary factors. A point mutation (C677T) in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in homocysteine remethylation, has been reported to render the enzyme thermolabile and less active and has been associated with elevated tHcy in homozygous carriers (+/+ genotype) as well as with increased risk of premature cardiovascular disease.
Methods and Results We investigated whether this mutation influences risk for myocardial infarction (MI) and plasma levels of tHcy and whether this effect may be modified by dietary folate intake in 190 MI cases and 188 control subjects from the Boston Area Health Study. Genotype frequencies were 37.8% for -/-, 47.8% for +/-, and 14.4% for +/+ in the control group and 50.0% for -/-, 34.7% for +/-, and 15.3% for +/+ in the case group. The relative risk for MI associated with the +/+ genotype (compared with +/- and -/-) was 1.1 (95% CI, 0.6 to 1.9; P=.8). Stratification by folate intake values above and below the median did not significantly alter these results. Plasma tHcy levels were 9.9±2.7 µmol/L in -/- individuals, 10.6±3.8 µmol/L in +/- individuals, and 9.1±2.3 µmol/L in +/+ individuals (Ptrend=NS; determined in 68 cases and 59 control subjects).
Conclusions Our data show that homozygosity for the C677T mutation in this largely white, middle-class US population is not associated with increased risk for MI, irrespective of folate intake. This suggests that this mutation does not represent a useful marker for increased cardiovascular risk in this and in similar populations.
Key Words: genes • risk factors • myocardial infarction
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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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|
|