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. (Blood. 2000;95:2780-2785)