Geographic Distribution of the 20210 G to A Prothrombin Variant

Summary

A variant in prothrombin (clotting factor II), a G to A transition at nucleotide position 20210, has recently been shown to be associated with the prothrombin plasma levels and the risk of both venous and arterial thrombosis. The purpose of this study was to investigate the prevalence of carriership of this mutation in various populations.

We combined data from 11 centres in nine countries, where tests for this mutation had been performed in groups representing the general population. We calculated an overall prevalence estimate, by a precision-weighted method, and, since the distribution of the prevalences did not appear homogeneous, by an unweighted average of the prevalences. We examined differences in the prevalences by geographical location and ethnic background as a possible explanation for the heterogeneity.

Among a total of 5527 individuals who had been tested, 111 heterozygous carriers of the 20210A mutation were found. The prevalence estimates varied from 0.7 to 4.0 between the centres. The overall prevalence estimate was 2.0 percent (CI95 1.4-2.6%). The variation around the summary estimate appeared more than was expected by chance alone, and this heterogeneity could be explained by geographic differences. In southern Europe, the prevalence was 3.0 percent (CI95 2.3 to 3.7%), nearly twice as high as the prevalence in northern Europe (1.7%, CI95 1.3 to 2.2%). The prothrombin variant appeared very rare in individuals from Asian and African descent.

The 20210A prothrombin variant is a common abnormality, with a prevalence of carriership between one and four percent. It is more common in southern than in northern Europe. Since this distribution within Europe is very different to that of another prothrombotic mutation (factor V Leiden or factor V R506Q), founder effects are the most likely explanation for the geographical distribution of both mutations.

• References

• 1 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 2 Degen SJ, Davie EW. Nucleotide sequence of the gene for human prothrombin. Biochemistry 1987; 26: 6165-77.
• 3 Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997; 90: 1747-50.
• 4 Doggen CJM, Manger Cats V, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998 (in press).
• 5 Franco RF, Trip MD, ten Cate H, Prins MH, Kastelein JJP, Reitsma PH. The prevalence of the 20210 G>A mutation in the 3’-untranslated region of the prothrombin gene in patients with premature coronary artery disease (abstract). Thromb Haemost 1997; Suppl: 769-70.
• 6 Alhenc-Gelas M, Le Cam-Duchez V, Emmerich J, Frebourg T, Fiessinger JN, Borg JY, Aiach M. The 20210A allele of the prothrombin gene is not frequently associated with the factor V Arg 506 to Gln mutation in thrombophilic families. Blood 1997; 90: 1711.
• 7 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-2.
• 8 Watzke HH, Schüttrumpf J, Graf S, Huber K, Panzer S. Increased prevalence of a polymorphism in the gene coding for human prothrombin in patients with coronary heart disease. Thromb Res 1997; 87: 521-6.
• 9 Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilia and is not increased in frequency in arterial disease. Arterioscler Thromb Vasc Biol. 1997 (in press).
• 10 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
• 11 Makris M, Preston FE, Beauchamp NJ, Hampton KK, Daly ME, Cooper P, Bayliss P, Peake IR. Co-inheritance of the 20210A allele of the prothrombin gene increases the thrombotic risk in subjects with familial thrombophilia (abstract). Thromb Haemost 1997; Suppl: 165.
• 12 Cox MJ, Rees DC, Martinson JJ, Clegg JB. Evidence for a single origin of factor V Leiden. Br J Haematol 1996; 92: 1022-5.
• 13 CIBA-GEIGY AG. Wissentschaftliche Tabellen Geigy: Teilband Statistik. Basel: CIBA-GEIGY; 1980
• 14 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297-301.
• 15 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
• 16 Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, Brenner B, Eldor A, Seligsohn U. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997; 2: 397-402.
• 17 Zivelin A, Rosenberg N, Dardik R, Amit Y, Kenet G, Kornbrot N, Fridman A, Seligsohn U. A low frequency of two genetic risk factors for thrombosis in Yemenite-jews who manifest a decreased incidence of coronary artery disease (abstract). Thromb Haemost 1997; Suppl: 222-3.
• 18 Arruda VR, Von Zuben PM, Chiaparini LC, Annichino-Bizacchi JM, Costa FF. The mutation Ala677>Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818-21.