The Prothrombotic Polymorphism Prothrombin G20210A is an ancestral mutation that arose in Caucasians approximately 20,000 years ago

The prothrombotic prothrombin G20210A polymorphism is associated with increased plasma levels of prothrombin, it confers a 2–5 fold increase in the risk of venous thromboembolism and is prevalent in Caucasians. We previously showed that prothrombin G20210A originated in a single ancestral founder (Zivelin et al. Blood 92:1119, 1998[Abstract/Free Full Text]). In this study we estimated the age of the G20210A polymorphism by assessing linkage disequilibrium (LD) between A20210 and 9 microsatellites markers or 5 SNPs located upstream and downstream of the prothrombin gene (Figure). The study group included 93 unrelated A20210 homozygotes (21 Israelis, 19 French, 17 Italians, 17 Austrians, 16 Dutch and 3 Germans) and 63 unrelated healthy Caucasian homozygotes for G20210 [GenBank] . Calculation of the mutation age was done by the DMLE+ program (Reeve and Rannala, Bioinformatics 18:894, 2002[Abstract/Free Full Text]), which allows Bayesian inference of mutation age based on observed LD at multiple genetic markers. Assuming 20 years as a generation, analysis of the microsatellite markers yielded an estimated age of 19,750 years (95% CI 16,200–29,500), and analysis of the SNPs yielded an estimated age of 20,500 years (95% CI of 14,700–27,950). We previously estimated by a different method (Risch et al. Nature Gen 9:152, 1995[Medline]) that the age of factor V Leiden, also prevalent only in Caucasians, is 21,000–34,000 years (Zivelin et al. Blood 89:397, 1997[Abstract/Free Full Text]). In the present study we recalculated the age of factor V Leiden by the DMLE+ program in 117 homozygous for factor V Leiden and 160 controls and obtained a value of 20,600 years (95% CI of 15,400–29,800). These data suggest that both relatively common prothrombotic polymorphisms occurred about 20,000 years before our time following the evolutionary divergence of Africans from Non-Africans and of Caucasians from Oriental subpopulation