A genetic variation in the 3'-untranslated region of the
prothrombin mRNA (20210 G/A) has recently been reported to be associated with elevated plasma
prothrombin levels and with an increased incidence of
venous thrombosis. We determined the frequency of this mutation, the detection of which was improved by allele-specific amplification of exon 14 and by denaturing gradients (denaturing gradient gel electrophoresis), in cohorts of patients affected by
venous thrombosis (n = 132) or by coronary or
cerebrovascular diseases (n = 195) and in normal subjects from various populations. An overlapping frequency of the heterozygous genotype (4%) was found in normal subjects from Italy and Cyprus, and no carrier was detected in 40 subjects of Indian or Somali origin. The 20210 GA heterozygous genotype was not increased in frequency in patients with arterial disease. In contrast, the GA genotype was associated (P = .007) with
venous thrombosis both in simple heterozygotes (16%) with a family history of
thrombosis as well as in double heterozygotes (14%) for other known thrombophilic defects. A synergic interaction between the
prothrombin 20210 GA genotype and the
factor V Leiden mutation, both potentially affecting the
prothrombinase complex, was suggested by the early onset of
thrombosis (median age 22 years) in doubly heterozygous patients. The association of the 20210 A allele with higher
prothrombin levels was confirmed in the Italian population. However, the
prothrombin assay does not allow an efficient preselection of patients for the
DNA analysis.