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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.

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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.


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