The 20210 G -> A mutation in the 3 '-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease

A sequence variation in the 3'-untranslated region of the prothrombin (PT) gene (20210 G-->A) was recently claimed to be associated with elevated plas ma prothrombin levels and an increased risk for venous and arterial thrombo sis, We examined the prevalence of the 20210 A allele in the prothrombin ge ne in 400 healthy controls and in 263 patients with proven premature athero sclerotic disease. In addition, we measured prothrombin, prothrombin fragme nt 1+2, thrombin-antithrombin (TAT) complex and D-dimer levels in plasma fr om carrier and non-carrier patients. The frequency of the variant allele wa s 1% in the control subjects and 2.7% in the patient group, yielding a rela tive risk (RR) for the 20210 A allele of 2.7 (95% CI 0.8-9.4). All heterozy gotes in the patient group were found to have had a myocardial infarction ( MI), yielding a RR for MI of 4.2 (95% CI 1.2-14.6). Plasma prothrombin leve ls in carriers (126 +/- 10) were higher than in non-carriers (103 +/-1, P=0 .02). The levels of TAT complexes (16 +/- 9 v 6 +/- 1 mu g/ml, P=0.02) as w ell as of prothrombin fragment 1 + 2 (1.5 +/- 0.3 v 1.0 +/- 0.1 nmol/l, P=0 .02) were also elevated in carriers of the mutation. Our findings suggest t hat the 20210 G-->A mutation in the prothrombin gene is a genetic risk fact or for MI. In addition, our data provide evidence for an association of the mutation with excessive thrombin generation, which may contribute to the u nderstanding of its role in venous and arterial disease.