Protective effect of a thrombin receptor (protease-activated receptor 1) gene polymorphism toward venous thromboembolism

The human protease-activated receptor 1 (PAR-1) is activated by thrombin at the surface of platelets and endothelial cells, 2 cells that are implicate d in hemostasis and thrombosis. We studied the PAR-1 gene in a large case-c ontrol study from the Paris Thrombosis Study (PATHROS), and the possible im plication of polymorphisms in venous thromboembolism was evaluated. Two pol ymorphisms were found in the 5' regulatory region. The first is a C to T tr ansition that is 1426 nucleotides upstream from the translation start site (-1426 C/T), and the second is a 13-bp insertion repeating the preceding -5 06 5'-CGGCCGCGGGAAG-3' sequence (-506 I/D, where I indicates insertion and D indicates deletion), a putative cia-acting element of the Ets family. The third polymorphism is an A to T transversion in the intervening sequence ( IVS) that is 14 nucleotides upstream from the exon 2 start site (IVS-14 A/T ), The distribution of the 3 polymorphisms was otherwise similar in the 250 cases and the 1214 controls. A noteworthy sex heterogeneity led us to anal yze men and women separately with regard to the -506 I/D polymorphism. We f ound that allele I was less frequent in male cases than in male controls (0 .154 versus 0.247, P<0.01), with an odds ratio at 0.52 (95% CI 0.32 to 0.82 , P<0.01). Furthermore, a reduction of prothrombin fragment 1+2 levels was observed in homozygous carriers of allele -505 1 (P=0.04). Altogether these data suggested a protective effect in men of -506 I/D polymorphism for ven ous thromboembolism.