Thermolabile Methylenetetrahydrofolate Reductase in Coronary Artery Disease

Author:

Kluijtmans Leo A. J.1,Kastelein John J. P.1,Lindemans Jan1,Boers Godfried H. J.1,Heil Sandra G.1,Bruschke Albert V. G.1,Jukema J. Wouter1,van den Heuvel Lambert P. W. J.1,Trijbels Frans J. M.1,Boerma Geert J. M.1,Verheugt Freek W. A.1,Willems Frank1,Blom Henk J.1

Affiliation:

1. 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.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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