Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis

José Manuel Soria, Laura Almasy, Juan Carlos Souto, Isabel Tirado, Montserrat Borell, José Mateo, Susan Slifer, William Stone, John Blangero, Jordi Fontcuberta

    Research output: Contribution to journalArticlepeer-review

    108 Scopus citations


    Association studies suggest that the G20210A mutation (G to A substitution at nucleotide position 20210) in the prothrombin gene (PT) is associated with increased plasma prothrombin activity and with increased risk for venous thromboembolism. To test directly for linkage between this PT variant and plasma prothrombin activity we performed a family-based study. The G20210A genotypes and plasma prothrombin activity levels were determined in 435 individuals belonging to 22 extended Spanish families. The sample was composed of 388 homozygous (G/G) normal individuals and 43 heterozygote (G/A) and 4 homozygote (A/A) carriers for the G20210A mutation. The results of variance-component linkage analysis yielded a highly significant lod score of 3.6 (P = 2.4 x 10-5) between this mutation and a quantitative trait locus (QTL)that influences prothrombin activity. Importantly, a conditional linkage analysis that simultaneously accounted for association with the G20210A variant completely eliminated the linkage signal, which indicates that this mutation affects the function of the prothrombin gene. Additionally, a bivariate linkage analysis of plasma prothrombin activity and thrombosis significantly improved the linkage signal for prothrombin activity (lod score = 4.7; P = 1.5 x 10-6) and provided strong evidence that this QTL has a pleiotropic effect on the risk of thrombosis (lod score = 2.43; P = .0004). These results represent the first direct genetic evidence that a QTL in the PT gene influences prothrombin activity levels and susceptibility to thrombosis and strongly support the conclusion that G20210A is a functional polymorphism. (C) 2000 by The American Society of Hematology.

    Original languageEnglish (US)
    Pages (from-to)2780-2785
    Number of pages6
    Issue number9
    StatePublished - May 1 2000

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology


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