C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: Results from genome-wide association and gene expression analyses followed by case-control studies

Alfonso Buil, David Alexandre Trégouët, Juan Carlos Souto, Noémie Saut, Marine Germain, Maxime Rotival, Laurence Tiret, Françcois Cambien, Mark Lathrop, Tanja Zeller, Marie Christine Alessi, Santiago Rodriguez De Cordoba, Thomas Münzel, Philipp Wild, Jordi Fontcuberta, France Gagnon, Joseph Emmerich, Laura Almasy, Stefan Blankenberg, José Manuel SoriaPierre Emmanuel Morange

    Research output: Contribution to journalArticle

    42 Scopus citations

    Abstract

    Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, α7β1, α 6β1, and α7β0, we conducted a genomewide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locuswere found genomewide significantly associated with α7β0 levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPBmRNAexpression. The allele associated with increased α7β0 plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated.

    Original languageEnglish (US)
    Pages (from-to)4644-4650
    Number of pages7
    JournalBlood
    Volume115
    Issue number23
    DOIs
    StatePublished - Jun 10 2010

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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    Buil, A., Trégouët, D. A., Souto, J. C., Saut, N., Germain, M., Rotival, M., Tiret, L., Cambien, F., Lathrop, M., Zeller, T., Alessi, M. C., De Cordoba, S. R., Münzel, T., Wild, P., Fontcuberta, J., Gagnon, F., Emmerich, J., Almasy, L., Blankenberg, S., ... Morange, P. E. (2010). C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: Results from genome-wide association and gene expression analyses followed by case-control studies. Blood, 115(23), 4644-4650. https://doi.org/10.1182/blood-2010-01-263038