The A20210 Allele of the Prothrombin Gene Is Frequently Associated With the Factor V Arg 506 to Gln Mutation But Not With Protein S Deficiency in Thrombophilic Families

To the Editor:

A genetic variation in the 3′-untranslated region of the prothrombin gene (G to A transition at position 20210) has recently been linked to increased plasma prothrombin levels and an enhanced risk of venous thrombosis.1 The A20210 allele is present in 5.0% to 7.3% of venous thrombosis patients and in 1.2% to 2.8% of healthy controls.1-6 Familial thrombophilia has been shown to be a complex genetic disorder often caused by the segregation of two or more gene defects.7,8 Thus, individuals with combined genetic defects are at higher risk of thrombosis than those with single gene defects. However, Alhenc-Gelas et al6 did not find any patients with the A20210 allele of the prothrombin gene among 288 French subjects belonging to 26 thrombophilic families with activated protein C (APC)-resistance, suggesting a lack of gene-gene interaction between the prothrombin and factor V gene defects. To further investigate this particular gene-gene interaction, we have studied the A20210 allele of the prothrombin gene in Swedish thrombophilic families with APC-resistance and protein S deficiency.

We tested 332 individuals belonging to 53 APC-resistant families for the FV:R506Q mutation and the A20210 allele of the prothrombin gene as described.3 8 In 20 individuals, protein S deficiency was present. The A20210 allele of the prothrombin gene was found in 7 of the 53 (13%) APC-resistant families. Of 29 (24 heterozygotes and 5 homozygotes) FV:R506Q-positive index cases available for testing, 3 (10%) carried the A20210 allele in heterozygous form, which is significantly higher than the 1.8% (5/282) found among unrelated healthy controls (P = .0056). In total, 17 of the 332 (5%) family members were heterozygous carriers of the A20210 allele, of which 8 were also heterozygous for the FV:R506Q mutation (Table1). Combined heterozygosity for the two gene defects tended to be more severe than single gene defects also after exclusion of the 20 protein S-deficient patients (Table 1). In fact, combined heterozygosity for the factor V and prothrombin gene mutations appeared as severe as homozygosity for the FV:R506Q allele, although the confidence intervals were rather wide. Individuals with combined gene defects tended to be younger at first thrombotic event as compared with individuals with isolated FV:R506Q mutation, although the difference did not reach significance (28 ± 3 v 37 ± 15 years, P = .34).

It was noteworthy that the two individuals with combined protein S deficiency and the A20210 were asymptomatic, although they had been exposed to circumstantial risk factors (Table 1). To further investigate the possible gene-gene interaction between the A20210 allele and protein S deficiency, we screened 78 symptomatic protein S-deficient individuals from 28 unrelated thrombophilic families. Protein S deficiency was defined as previously described.9Seventy-four of the protein S-deficient individuals belonged to 24 families with inherited protein S deficiency. The remaining 4 protein S-deficient patients came from families in which the inherited nature of protein S deficiency was not possible to confirm. Surprisingly, none of the 78 thrombotic protein S-deficient patients carried the A20210 allele. In comparison, the FV:R506Q mutation was found in 10 of the 28 (36%) protein S-deficient families. In total, 16 of the 78 (20%) thrombotic protein S-deficient patients were carriers of the FV:R506Q mutation.

We conclude that the prothrombin A 20210 allele of the prothrombin gene is a common additional thrombotic risk factor in Swedish thrombophilic families with APC-resistance but not in symptomatic protein S-deficient patients. The thrombotic risk of individuals with combined prothrombin and factor V gene defects appears to be high, and this combination adds to the growing list of gene-gene interaction causing familial thrombophilia. In contrast, none of the 78 thrombotic protein S-deficient patients from 28 unrelated families carried the A20210 allele. The apparent lack of interaction between the protein S and the prothrombin gene defects is interesting but needs to be confirmed by others due to the limited number of protein S-deficient families in our study.