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Clinical Chemistry 54: 833-840, 2008. First published March 20, 2008; 10.1373/clinchem.2007.096479
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(Clinical Chemistry. 2008;54:833-840.)
© 2008 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Genetic Variants of Tumor Necrosis Factor Superfamily, Member 4 (TNFSF4), and Risk of Incident Atherothrombosis and Venous Thromboembolism

Anders Mälarstig1, Per Eriksson1, Lynda Rose2, Kirsti A. Diehl2, Anders Hamsten1, Paul M Ridker2 and Robert Y.L. Zee2,a

1 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden; 2 Center for Cardiovascular Disease Prevention, and the Leducq Center for Molecular and Genetic Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

aAddress correspondence to this author at: Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail rzee{at}rics.bwh.harvard.edu.

Background: Recent data have implicated tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4) gene variation in myocardial infarction in women; however, no prospective data are available on either incident arterial or venous disorders.

Methods: We evaluated 2 previously characterized TNFSF4 gene variants (–921C>T and dbSNP rs3850641) with a) incident arterial events using a prospective case-cohort design with 344 incident CVD cases and 2254 control participants, all white, drawn from the Women’s Health Study cohort with 10 years of follow-up, and b) venous thromboembolism (VTE) risk using a nested, matched case-control design of 108 white male pairs (drawn from the Physicians’ Health Study cohort) and a case-cohort design of white female participants consisting of 125 cases and 2269 controls (drawn from the Women’s Health Study cohort), analyzed separately.

Results: Genotype distributions were in Hardy-Weinberg equilibrium. Results from a marker-by-marker regression analysis, adjusting for traditional risk factors, showed a significant association of –921C>T with an increased risk of VTE in women (additive: odds ratio 1.86; 95% CI 1.17–2.92, P = 0.008) in women. Furthermore, using a haplotype-based regression analysis, haplotype C-G was associated with a reduced risk of VTE relative to the referent haplotype, C-A (odds ratio 0.50; 95% CI 0.27–0.92; P = 0.02). In contrast, we found little evidence for an association of the variants/haplotypes with risk of VTE in men or CVD risk in women (as previously reported).

Conclusions: Our present findings, if corroborated in other prospective investigations, suggest that the TNFSF4 variants tested may be useful indicators for assessing the risk of venous thromboembolism.






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