Absence of Prothrombin Mutation in Inuit (Greenland Eskimos)

Association between variations in the genes of protein S, protein C, fibrinogen and antithrombin and increased risk of deep vein thrombosis (DVT) has previously been described. More recently, a mutation in coagulation factor V (factor V Leiden mutation: R/Q506) has been identified as the most common hereditary risk factor for venous thrombosis. For the factor V Leiden point mutation we showed that this mutation was absent in Inuit (Greenland Eskimos), a population with a low incidence of acute ischaemic heart disease and venous thromboembolism (1, 2). Post-surgery DVT and DVT after fractures are rarely observed in the Inuit. We also observed that the frequency of genetic polymorphisms in hemostatic genes (fibrinogen aand b-genes, platelet glycoprotein IIIa gene and factor VII gene) were different in Greenland Inuit and Caucasians, and for these genes the frequency of the potentially high risk allele was lower in the Inuit (3-5). It has recently been reported that variation in the 3’-untranslated region of the prothrombin gene (20210G/A) is associated with an increased risk of DVT (Table) (6). The 20210A-allele was found in 18% of selected patients with a personal and family history of venous thrombosis, in 6.2% of unselected patients with DVT and in 2.3% of healthy control subjects. In the Danish population the 20210A-allele is present in 1.0% of healthy control subjects (n = 608) (unpublished results). Carriers of the 20210A-allele had 26% higher plasma prothrombin levels than non-carriers. This suggests that the 20210G/A polymorphism can contribute to the regulation of plasma prothrombin levels and thus to a prothrombotic state, but the underlying mechanism of this association has not yet been elucidated (6). We have studied the prothrombin polymorphism in a group of 478 unrelated Greenland Inuit (216 men and 262 women), aged 15 to 64 y. In order to “dilute” a possible effect of migration we studied exclusively individuals born in Greenland by Inuit mothers also born in Greenland. We determined the prothrombin 20210G/A genotype by amplification of the 3’-untranslated region of the prothrombin gene by PCR and digestion of the fragment with HindIII (6). In each PCR run samples with known genotypes were included. As quality control, we also reanalyzed 10% of the Inuit samples and the results were confirmed. None of the subjects in our Inuit population had a history of cardiovascular diseases or thromboembolic diseases and none was carrier of the 20210A allele (Table). It cannot be excluded that also environmental factors contribute to the low incidence of vascular disease in the Inuit. For example, it is known that their diet contains more unsaturated fatty acids, and that the Inuit smoke more and have a higher alcohol intake. However, these factors are more likely to affect arterial thrombosis and not venous thrombosis. Thus, our data further support the hypothesis that genetic variation in the Inuit may contribute to their low prevalence of acute ischaemic heart disease and venous thromboembolism.