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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:942.)
© 2006 American Heart Association, Inc.

Thrombosis

Thrombomodulin Gene Polymorphisms and Haplotypes and the Risk of Cardiovascular Events

A Prospective Follow-Up Study

K. Auro; K. Komulainen; M. Alanne; K. Silander; L. Peltonen; M. Perola; V. Salomaa

From the Department of Molecular Medicine (K.A., K.K., M.A., K.S., L.P., M.P.), KTL, Helsinki, Finland; Department of Epidemiology and Health Promotion (V.S.), KTL, Helsinki, Finland; and Department of Medical Genetics (L.P., M.P.), University of Helsinki, Finland.

Correspondence to Dr Veikko Salomaa, Department of Epidemiology and Health Promotion, KTL-National Public Health Institute Mannerheimintie 166, FI-00300 Helsinki Finland. E-mail veikko.salomaa{at}ktl.fi

Background— Thrombomodulin is an anticoagulant expressed during endothelial activation and damage. To address the potential role of allelic variants of thrombomodulin gene in the pathogenesis of cardiovascular diseases, we analyzed in a prospective follow-up study 8 single-nucleotide polymorphisms (SNPs) across the thrombomodulin locus, covering all common (>5%) haplotypes.

Methods and Results— Two separate, stratified random samples of men and women 25 to 74 years of age were examined in Finland in 1992 and 1997. The total sample size was 14 140 individuals, with 7 (1997 cohort) to 10 (1992 cohort) years of follow-up. Altogether, 662 individuals had a history of cardiovascular events already at baseline. During the follow-up, 401 incident coronary events and 148 incident ischemic strokes were observed. The alleles and common haplotypes of 8 SNPs were tested in Cox proportional hazards models using incident coronary events, incident ischemic strokes, and total mortality as end points. None of the SNPs or major SNP haplotypes showed consistent association with the end points analyzed in the combined data.

Conclusions— Results from this prospective, population-based study suggest that common allelic variants of the thrombomodulin gene may not significantly contribute to the risk of cardiovascular events at the population level.

Thrombomodulin, a natural anticoagulant and a biological marker for endothelial activation and damage, has been suggested to contribute to the pathogenesis of cardiovascular diseases. In a prospective follow-up study combining 2 large, independent Finnish cohorts, common allelic variants of the thrombomodulin gene did not show consistent association with the risk of cardiovascular events.

Key Words: coronary artery disease • stroke • thrombosis • genetic mutations • epidemiology