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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 9, 2006 Accepted November 3, 2006 A sequence variation scan of the coagulation factor (F)VIII structural gene and associations with plasma FVIII activity (FVIII:C) levels Kevin R. Viel, Deepa K. Machiah, Diane M. Warren, Manana Khachidze, Alfonso Buil, Karl Fernstrom, Juan C. Souto, Jaun M Peralta, Todd Smith, John Blangero, Sandra Porter, Stephen T. Warren, Jordi Fontcuberta, Jose M. Soria, William Dana Flanders, Laura Almasy, and Tom E. Howard* Dept of Pathology & Laboratory Medicine, Emory University, Atlanta, GA, United States Dept of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, United States Unitat d Hemostasia i Trombosi, Dept d Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Centro de Investigacion en Biologia Celular y Molecular, Universidad de Costa Rica, San Pedro, Costa Rica Geospiza Inc., Seattle, WA, United States Dept of Human Genetics, Emory University, Atlanta, GA, United States Dept of Epidemiology, Emory University, Atlanta, GA, United States * Corresponding author; email: thoward{at}emory.edu. Plasma FVIII:C is a highly heritable quantitative-trait that is strongly correlated with thrombosis risk. Polymorphisms within only one 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 non-hemophilic individuals representing seven 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 C92714G, a nonsynonymous-SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C. 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 = 0.016). Nevertheless, because the alleles of G56010A, a SNP within the 3'-splice-junction of intron-7, are strongly associated with C92714G 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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