A COMMON GENETIC-VARIATION IN THE 3'-UNTRANSLATED REGION OF THE PROTHROMBIN GENE IS ASSOCIATED WITH ELEVATED PLASMA PROTHROMBIN LEVELS AND AN INCREASE IN VENOUS THROMBOSIS

We have examined the prothrombin gene as a candidate gene for venous t hrombosis in selected patients with a documented familial history of v enous thrombophilia. All the exons and the 5'- and 3'-UT region of the prothrombin gene were analyzed by polymerase chain reaction and direc t sequencing in 28 probands. Except for known polymorphic sites, no de viations were found in the coding regions and the 5'-UT region. only o ne nucleotide change (a G to A transition) at position 20210 was ident ified in the sequence of the 3'-UT region. Eighteen percent of the pat ients had the 20210 AG genotype, as compared with 1% of a group of hea lthy controls (100 subjects). In a population-based case-control study , the 20210 A allele was identified as a common allele (allele frequen cy, 1.2%: 95% confidence interval, 0.5% to 1.8%), which increased the risk of venous thrombosis almost threefold (odds ratio, 2.8; 95% confi dence interval, 1.4 to 5.6), The risk of thrombosis increased for all ages and both sexes. An association was found between the presence of the 20210 A allele and elevated prothrombin levels. Most individuals ( 87%) with the 20210 A allele are in the highest quartile of plasma pro thrombin levels (>1.15 U/mL), Elevated prothrombin itself also was fo und to be a risk factor for venous thrombosis. (C) 1996 by The America n Society of Hematology.