A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels

Kevin R. Viel, Deepa K. Machiah, Diane M. Warren, Manana Khachidze, Alfonso Buil, Karl Fernstrom, Juan C. Souto, Juan M. Peralta, Todd Smith, John Blangero, Sandra Porter, Stephen T. Warren, Jordi Fontcuberta, Jose M. Soria, W. Dana Flanders, Laura Almasy, Tom E. Howard

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    76 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)3713-3724
    Number of pages12
    JournalBlood
    Volume109
    Issue number9
    DOIs
    StatePublished - May 1 2007

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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    Viel, K. R., Machiah, D. K., Warren, D. M., Khachidze, M., Buil, A., Fernstrom, K., Souto, J. C., Peralta, J. M., Smith, T., Blangero, J., Porter, S., Warren, S. T., Fontcuberta, J., Soria, J. M., Flanders, W. D., Almasy, L., & Howard, T. E. (2007). A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels. Blood, 109(9), 3713-3724. https://doi.org/10.1182/blood-2006-06-026104