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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 31, 2005 Accepted August 8, 2005 Genetic variation in the fibrinogen gamma gene increases the risk of deep venous thrombosis by reducing plasma fibrinogen ' levels Shirley Uitte de Willige, Marieke C de Visser, Jeanine J Houwing-Duistermaat, Frits R Rosendaal, Hans L Vos, and Rogier M Bertina* Hemostasis and Thrombosis Research Center, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands Hemostasis and Thrombosis Research Center, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands * Corresponding author; email: R.M.Bertina{at}lumc.nl. We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB) and gamma (FGG), total fibrinogen levels, fibrinogen ' (A/' plus '/') levels, and risk of deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging (ht) SNPs in this gene-cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombotic risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (OR=2.4, 95%CI:1.5-3.9). FGG-H2 was also associated with reduced fibrinogen ' levels and reduced fibrinogen '/total fibrinogen ratios. Multivariable analysis showed that reduced fibrinogen ' levels and elevated total fibrinogen levels were both associated with an increased risk of thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen '/total fibrinogen ratio (< 0.69) also increased the risk (OR=2.4, 95%CI:1.7-3.5). We propose that FGG-H2 influences thrombosis risk via htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring formation of A chain above that of ' chain. Fibrinogen ' contains a unique high-affinity non-substrate binding site for thrombin, which seems critical for the expression of the antithrombin activity which develops during fibrin formation (antithrombin I). 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. 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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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