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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4176-4183. Prepublished online as a Blood First Edition Paper on September 6, 2005; DOI 10.1182/blood-2005-05-2180. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-05-2180v1 106/13/4176    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Uitte de Willige, S. Articles by Bertina, R. M. Search for Related Content PubMed PubMed Citation Articles by Uitte de Willige, S. Articles by Bertina, R. M. Related Collections Clinical Trials and Observations Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen ' levels Shirley Uitte de Willige, Marieke C. H. de Visser, Jeanine J. Houwing-Duistermaat, Frits R. Rosendaal, Hans L. Vos, and Rogier M. Bertina From the Hemostasis and Thrombosis Research Center, Departments of Hematology, Medical Statistics, and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen ' (A/' plus '/') levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen ' levels and reduced ratios of fibrinogen ' to total fibrinogen. Multivariate analysis showed that reduced fibrinogen ' levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen ' to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5). We propose that FGG-H2 influences thrombosis risk through htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring the formation of A chain above that of ' chain. Fibrinogen ' contains a unique high-affinity, nonsubstrate binding site for thrombin, which seems critical for the expression of the antithrombin activity that develops during fibrin formation (antithrombin 1). CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M van Oijen, E Y L Cheung, C E M Geluk, A Hofman, P J Koudstaal, M M B Breteler, and M P de Maat Haplotypes of the fibrinogen gene and cerebral small vessel disease: the Rotterdam scan study J. Neurol. Neurosurg. Psychiatry, July 1, 2008; 79(7): 799 - 803. [Abstract] [Full Text] [PDF] E. Y.L. Cheung, S. U. de Willige, H. L. Vos, F. W.G. Leebeek, D. W.J. Dippel, R. M. Bertina, and M. P.M. de Maat Fibrinogen {gamma}' in Ischemic Stroke: A Case-Control Study Stroke, March 1, 2008; 39(3): 1033 - 1035. [Abstract] [Full Text] [PDF] J. C. Fredenburgh, A. R. Stafford, B. A. Leslie, and J. I. Weitz Bivalent Binding to {gamma}A/{gamma}'-Fibrin Engages Both Exosites of Thrombin and Protects It from Inhibition by the Antithrombin-Heparin Complex J. Biol. Chem., February 1, 2008; 283(5): 2470 - 2477. [Abstract] [Full Text] [PDF] J. R. Cerhan, S. M. Ansell, Z. S. Fredericksen, N. E. Kay, M. Liebow, T. G. Call, A. Dogan, J. M. Cunningham, A. H. Wang, W. Liu-Mares, et al. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma Blood, December 15, 2007; 110(13): 4455 - 4463. [Abstract] [Full Text] [PDF] R. L. Davis, M. W. Mosesson, B. A. Kerlin, J. A. Canner, F. B. Ruymann, and S. O. Brennan Fibrinogen Columbus: a novel gamma Gly200Val mutation causing hypofibrinogenemia in a family with associated thrombophilia Haematologica, August 1, 2007; 92(8): 1151 - 1152. [Abstract] [Full Text] [PDF] N. L. Smith, L. A. Hindorff, S. R. Heckbert, R. N. Lemaitre, K. D. Marciante, K. Rice, T. Lumley, J. C. Bis, K. L. Wiggins, F. R. Rosendaal, et al. Association of Genetic Variations With Nonfatal Venous Thrombosis in Postmenopausal Women JAMA, February 7, 2007; 297(5): 489 - 498. [Abstract] [Full Text] [PDF] S. U. de Willige, I. M. Rietveld, M. C.H. de Visser, H. L. Vos, and R. M. Bertina Polymorphism 10034C>T Is Located in a Functional Cleavage Stimulation Factor (CstF) Binding Site of the Fibrinogen Gamma Gene and Influences the {gamma}'/{gamma}A mRNA Ratio. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 543 - 543. [Abstract] [PDF] T. Iwaki, M. J. Sandoval-Cooper, M. Brechmann, V. A. Ploplis, and F. J. Castellino A fibrinogen deficiency accelerates the initiation of LDL cholesterol-driven atherosclerosis via thrombin generation and platelet activation in genetically predisposed mice Blood, May 15, 2006; 107(10): 3883 - 3891. [Abstract] [Full Text] [PDF]

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