A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility

José Manuel Soria, Laura Almasy, Joan Caries Souto, Alfonso Buil, Elisabeth Martínez-Sánchez, José Mateo, Montserrat Borrell, William H. Stone, Mark Lathrop, Jordi Fontcuberta, John Blangero

    Research output: Contribution to journalArticle

    71 Scopus citations

    Abstract

    Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P = 3.08 × 10-5). However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1). This indicates that apart from the FVL,the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences the risk of thrombosis (P = .0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and factor VIII (FVIII) levels as well as susceptibility to thrombosis. Importantly, there are no known thrombosis-related candidate genes in this region, implying that this QTL represents a completely novel thrombosis risk factor.

    Original languageEnglish (US)
    Pages (from-to)163-167
    Number of pages5
    JournalBlood
    Volume101
    Issue number1
    DOIs
    StatePublished - Jan 1 2003

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Fingerprint Dive into the research topics of 'A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility'. Together they form a unique fingerprint.

  • Cite this

    Soria, J. M., Almasy, L., Souto, J. C., Buil, A., Martínez-Sánchez, E., Mateo, J., Borrell, M., Stone, W. H., Lathrop, M., Fontcuberta, J., & Blangero, J. (2003). A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. Blood, 101(1), 163-167. https://doi.org/10.1182/blood-2002-06-1792