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
). 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. Calculation of the mutation age was done by the DMLE+ program (
Reeve and Rannala,
Bioinformatics
18
:
894
,
2002
), 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
) 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
). 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 subpopulations.

Figure
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Figure

Topics:
european continental ancestry group, mutation, polymorphism, prothrombin g20210a, factor v leiden, prothrombin, venous thromboembolism, genetic markers, homozygote, microsatellite repeats

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2005, The American Society of Hematology
2005
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