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American Journal of Clinical Nutrition, Vol. 77, No. 1, 63-70, January 2003
© 2003 American Society for Clinical Nutrition

Original Research Communication

Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project1,2,3

Raymond Meleady, Per M Ueland, Henk Blom, Alexander S Whitehead, Helga Refsum, Leslie E Daly, Stein Emil Vollset, Cait Donohue, Belinda Giesendorf, Ian M Graham, Arve Ulvik, Ying Zhang and Anne-Lise Bjorke Monsen and the EC Concerted Action Project: Homocysteine and Vascular Disease

1 From the Department of Cardiology, Adelaide-Meath Hospital, Incorporating the National Children’s Hospital (RM and IMG), and the Department of Genetics (CD and ASW), Trinity College, Dublin; the Locus for Homocysteine and Related Vitamins, Armauer Hansens Hus (PMU, HR, YZ, AU, and A-LBM), and the Division of Medical Statistics, Department of Public Health and Primary Health Care (SEV), University of Bergen, Bergen, Norway; the Department of Pediatrics, University Hospital, Nijmegen, Netherlands (HB and BG); the Department of Pharmacology and Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia (ASW); the Department of Public Health Medicine and Epidemiology, University College, Dublin (LED); and the Department of Epidemiology and Preventive Medicine, Royal College of Surgeons in Ireland (IMG). Members of the EC Concerted Action Project and their institutional affiliations are listed in the Acknowledgments.

Background: Homozygotes for the thermolabile mutation (TT genotype) of the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme have elevated plasma concentrations of the cardiovascular disease risk factor homocysteine, particularly if folate depleted.

Objective: We examined the relations between thermolabile MTHFR, plasma homocysteine, plasma folate, and vascular disease risk.

Design: This was a case-control comparison in 711 vascular disease cases and 747 controls from 9 European countries.

Results: The TT genotype was associated with higher homocysteine and lower plasma folate than the CC and CT genotypes in both cases and controls and a nonsignificant increase in vascular disease risk (1.26; 95% CI: 0.88, 1.81; P = 0.20). The frequency of the TT genotype in cases was not significantly different from that in controls (12.8% compared with 10.8%). After adjustment for traditional risk factors, the TT genotype was associated with an odds ratio of 1.48 (1.0, 2.20) for risk of vascular disease. This risk was attenuated after further adjustment for homocysteine. In subgroups with homocysteine concentrations >= 9 µmol/L, risk tended to be higher in CC than in TT subjects. However, CC subjects were characterized by a higher prevalence of the conventional risk factors associated with both elevated plasma homocysteine and serum creatinine. After adjustment, the risk of vascular disease associated with each genotype was not significantly different.

Conclusions: There was a strong graded association between homocysteine and vascular risk in all genotypes. MTHFR genotype is a key determinant of plasma total homocysteine concentrations. The initially nonsignificant risk estimate associated with the TT genotype was strengthened after adjustment for conventional cardiovascular disease risk factors but was attenuated after adjustment for plasma folate and total homocysteine. The modest risk increase conferred by the TT genotype is mediated mainly by increased total homocysteine and low plasma folate concentrations.

Key Words: Homocysteine • methylenetetrahydrofolate reductase • MTHFR • ischemic heart disease • vascular disease risk • folate • European Concerted Action Project




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