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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3713-3724. Prepublished online as a Blood First Edition Paper on January 5, 2007; DOI 10.1182/blood-2006-06-026104. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2006-06-026104v1 109/9/3713    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Viel, K. R. Articles by Howard, T. E. Search for Related Content PubMed PubMed Citation Articles by Viel, K. R. Articles by Howard, T. E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels Kevin R. Viel1,2, Deepa K. Machiah1, Diane M. Warren3, Manana Khachidze1, Alfonso Buil4, Karl Fernstrom1, Juan C. Souto4, Juan M. Peralta3,5, Todd Smith6, John Blangero3, Sandra Porter6, Stephen T. Warren7, Jordi Fontcuberta4, Jose M. Soria4, W. Dana Flanders2, Laura Almasy3, and Tom E. Howard1 1 Department of Pathology and Laboratory Medicine and 2 Department of Epidemiology, Emory University, Atlanta, GA; 3 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX; 4 Unitat d Hemostàsia i Trombosi, Departament d Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5 Centro de Investigacion en Biologia Celular y Molecular, Universidad de Costa Rica, San José, Costa Rica; 6 Geospiza, Seattle, WA; and 7 Department of Human Genetics, Emory University, Atlanta, GA Plasma factor VIII coagulant activity (FVIII:C) level is a highly heritable quantitative trait that is strongly correlated with thrombosis risk. Polymorphisms within only 1 gene, the ABO blood-group locus, have been unequivocally demonstrated to contribute to the broad population variability observed for this trait. Because less than 2.5% of the structural FVIII gene (F8) has been examined previously, we resequenced all known functional regions in 222 potentially distinct alleles from 137 unrelated nonhemophilic individuals representing 7 racial groups. Eighteen of the 47 variants identified, including 17 single-nucleotide polymorphisms (SNPs), were previously unknown. As the degree of linkage disequilibrium across F8 was weak overall, we used measured-genotype association analysis to evaluate the influence of each polymorphism on the FVIII:C levels in 398 subjects from 21 pedigrees known as the Genetic Analysis of Idiopathic Thrombophilia project (GAIT). Our results suggested that 92714C>G, a nonsynonymous SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C level. After accounting for important covariates, including age and ABO genotype, the association persisted with each C-allele additively increasing the FVIII:C level by 14.3 IU dL–1 (P = .016). Nevertheless, because the alleles of 56010G>A, a SNP within the 3' splice junction of intron 7, are strongly associated with 92714C>G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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