A Mutation in the Thrombomodulin Gene, 127 G to A Coding for Ala25Thr, and the Risk of Myocardial Infarction in Men

Carine J.M. Doggen, Gabriella Kunz, Frits R. Rosendaal, David A. Lane, Hans L. Vos, Peter J. Stubbs, Volkert Manger Cats, Helen A. Ireland

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Abstract

Thrombomodulin is an endothelial cell surface receptor that trans-formsthe procoagulant thrombin into an anticoagulant. A mutation inthe thrombomodulin gene is a potential risk factor for venous andarterial thrombosis.We screened a region within the coding sequence of the thrombo-modulingene by single-strand conformation polymorphism analysis(SSCP) in a pilot study of 104 patients with myocardial infarction and104 age, sex and race matched controls. We identified a 127 G to Amutation in the gene, which predicts an Ala25Thr substitution, in 2 outof 104 patients (1 man and 1 woman) with myocardial infarction but inno controls. We assessed the risk of myocardial infarction associatedwith the mutation in a larger “Study of Myocardial Infarctions Leiden”(SMILE). Among 560 men with a first myocardial infarction before theage of 70, 12 were carriers of the Ala25Thr substitution. In a controlgroup of 646 men, frequency-matched for age, seven were carriers ofthe Ala25Thr substitution. The allelic frequencies were 1.07% amongpatients and 0.54% among controls suggesting risk associated with themutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1].In patients aged below 50, the predicted risk was almost seven times in-creased(OR 6.5, CI 0.8-54.2). In the presence of additional risk factors,such as smoking and a metabolic risk factor, the predicted riskincreased to 9-fold (OR 8.8, CI 1.8-42.2) and 4-fold (OR 4.4,CI 0.9-21.3), respectively.While not conclusive, these results strongly suggest that theAla25Thr substitution is a risk factor for myocardial infarction, espe-ciallyin young men, and when in the presence of additional risk factors.
Original languageEnglish
Pages (from-to)743-748
JournalThrombosis and haemostasis
Volume80
Issue number5
DOIs
Publication statusPublished - 1998
Externally publishedYes

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