The Heterozygous 20210 G/A Prothrombin Genotype Is Associated With Early Venous Thrombosis in Inherited Thrombophilias and Is Not Increased in Frequency in Artery Disease

Abstract

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.

Study of the Prothrombin Gene 20201 GA Variant in FV:Q 506 Carriers in Relationship to the Presence or Absence of Juvenile Venous Thromboembolism

“…Similar to our findings, Ferraresi et al 17 found a significant increase in the frequency of the 20210 GA genotype in thrombophilic patients doubly heterozygous for other known thrombophilic defects (14%), including FV Leiden, but not in their asymptomatic relatives (3%). Zöller et al 37 reported that none of 78 thrombotic protein S-deficient patients carried the FII 20210 GA variant, whereas of 29 FV:R506Q-positive index cases, 3 (10%) were carriers of the 20210 A allele in heterozygous form.…”

“…In summary, the data from our investigation as well as from previous studies 13,17,37 and FII 20210 GA found in our patients who experienced juvenile VTE supports the hypothesis that the presence of 2 inherited prothrombotic risk factors might lead to thromboembolic manifestations at young ages with an increasing rate of spontaneous onset manifestations. Thus, comprehensive investigations of the prothrombin 20210 A allele are important for interpretation of the additional thrombotic risk in patients with other genetic defects predisposing for thrombosis.…”

“…Accordingly, heterozygosity for the prothrombin gene variant 20210 GA has been identified in Յ18% of selected patients with a personal and family history of VTE and in 5% to 7.1% of unselected patients with VTE. [13][14][15][16][17] For heterozygous carriers of the FII A20210 allele, odds ratios for thrombosis of Ϸ3 to 4 have been reported. [13][14][15][16] In comparison, the odds ratio for thrombosis has been calculated to be 3-to 8-fold for those carrying the FV mutation in a heterozygous form and 30-to 140-fold in homozygous individuals.…”

“…13 Carriers of the A20210 allele were found in 0% to 4% of healthy controls and in 5% to 19% of patients with VTE. [13][14][15][16][17][18] Whereas the cosegregation of the FV:R506Q mutation and other well-established thrombotic risk factors has been investigated in greater detail, scant information is available concerning the coexistence of both of the most common prothrombotic gene variants, FII 20210 GA and FV 1691 GA. This prompted us to evaluate the prevalence of the prothrombin gene variant G20210A among patients with juvenile VTE and to assess its importance as an additional prothrombotic risk allele in patients carrying the FV:R506Q mutation.…”

Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation

“…[1][2][3] The prevalence of the 20210A allele in the Caucasian population is about 2% but this is higher in Southern Europe. 4 Carriers of the mutant allele present with higher prothrombin levels in plasma, probably due to a change in polyadenylation efficiency, 5 and it has been suggested that this increase is responsible for the higher risk of thrombosis in carriers of the 20210A variant.…”