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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2780-2785
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, and
Jordi Fontcuberta
From the Unitat d'Hemostàsia i Trombosi. Hospital de la Santa
Creu i Sant Pau, Barcelona, Spain; the Department of Genetics,
Southwest Foundation for Biomedical Research, San Antonio, TX; and the
Department of Biology, Trinity University, San Antonio, TX.
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 × 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 × 106) 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.
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