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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:585.)
© 2000 American Heart Association, Inc.

Thrombosis

Protective Effect of a Thrombin Receptor (Protease-Activated Receptor 1) Gene Polymorphism Toward Venous Thromboembolism

Emmanuel Arnaud; Viviane Nicaud; Odette Poirier; Francine Rendu; Martine Alhenc-Gelas; Jean-Noël Fiessinger; Joseph Emmerich; Martine Aiach

From the Laboratoire d’Hémostase and Service des Maladies Vasculaires (E.A., M.A.-G., J.-N.F., J.E., M.A.), Hôpital Broussais-AP-HP; Unité INSERM 428 (E.A., F.R., M.A.-G., J.-N.F., J.E., M.A.), Faculté de Pharmacie, Université René Descartes; and Unité INSERM 525 (V.N., O.P.), Paris, France.

Correspondence to Dr Emmanuel Arnaud, Laboratoire d’Hémostase, Hôpital Broussais, 96, rue Didot, F-75674 Paris Cedex 14, France. E-mail emmanuel.arnaud{at}brs.ap-hop-paris.fr

Abstract—The human protease-activated receptor 1 (PAR-1) is activated by thrombin at the surface of platelets and endothelial cells, 2 cells that are implicated in hemostasis and thrombosis. We studied the PAR-1 gene in a large case-control study from the Paris Thrombosis Study (PATHROS), and the possible implication of polymorphisms in venous thromboembolism was evaluated. Two polymorphisms were found in the 5' regulatory region. The first is a C to T transition that is 1426 nucleotides upstream from the translation start site (-1426 C/T), and the second is a 13-bp insertion repeating the preceding -506 5'-CGGCCGCGGGAAG-3' sequence (-506 I/D, where I indicates insertion and D indicates deletion), a putative cis-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 analyze men and women separately with regard to the -506 I/D polymorphism. We found 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 -506 I (P=0.04). Altogether, these data suggested a protective effect in men of -506 I/D polymorphism for venous thromboembolism.

Key Words: human thrombin receptor • gene polymorphism • venous thromboembolism

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