(Circulation. 1996;94:2154-2158.)
© 1996 American Heart Association, Inc.
Articles |
Homocysteine and Risk of Premature Coronary Heart Disease
Evidence for a Common Gene Mutation
the Department of Genetics, Trinity College, Dublin 2, Ireland (P.M.G., D.C.S., A.S.W.); Department of Cardiology, Adelaide Hospital, Trinity College, Dublin (R.M., I.M.G.); Department of Epidemiology and Preventive Medicine, Royal College of Surgeons, Dublin, Ireland (I.M.G.); Department of Medicine, Toa Payoh Hospital, Singapore (K.S.T.); Department of Epidemiology and Public Health, The Queen's University of Belfast, Northern Ireland (D.M., A.E.); and Departments of Human Genetics, Pediatrics, and Biology, McGill University, Montreal, Quebec, Canada (R.R).
Correspondence to Prof A.S. Whitehead, Department of Genetics, Trinity College, Dublin 2, Ireland.
Background Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR). A common defective (thermolabile) variant of this enzyme is causally associated with elevated plasma homocysteine, itself an independent risk factor for coronary heart disease.
Methods and Results To examine the hypothesis that the allele (T) that codes for the thermolabile defect increases the risk of coronary heart disease, we studied 111 patients with clinical and objective investigational evidence of coronary heart disease and 105 control subjects. The frequencies of the thermolabile defect (T) in patients and control subjects were measured, and the prevalence of elevated plasma total homocysteine according to genotype was assessed. The frequency of the defective allele was higher in patients than in control subjects with an OR of 1.6 (95% CI, 1.1 to 2.4; P=.02). The OR in the coronary heart disease group for the homozygous TT genotype was 2.9 (95% CI, 1.2 to 7.2; P=.02); 17% of patients and 7% of control subjects had the TT genotype. Plasma total homocysteine levels were significantly associated with disease status, a relationship that matched the strength of the association between disease and homozygous inheritance of the defective enzyme.
Conclusions Homozygotes for the defective allele (T) are at increased risk of premature coronary heart disease. MTHFR, which modulates basal plasma homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion of the general population.
Key Words: coronary heart disease • homocysteine • MTHFR • mutation
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