Association between the Thr325Ile polymorphism of the thrombinactivatable fibrinolysis inhibitor and stroke in the Ludwigshafen Risk and Cardiovascular Health Study

Detlef H. Kozian; Martin Lorenz; Winfried März; Emmanuelle Cousin; Sandrine Mace; Jean-Francois Deleuze

doi:10.1160/TH09-10-0682

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(05): 976-983
DOI: 10.1160/TH09-10-0682

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Association between the Thr325Ile polymorphism of the thrombinactivatable fibrinolysis inhibitor and stroke in the Ludwigshafen Risk and Cardiovascular Health Study

Detlef H. Kozian

¹Sanofi-Aventis Deutschland GmbH, Therapeutic Department Thrombosis & Angiogenesis, Frankfurt, Germany

,

Martin Lorenz

¹Sanofi-Aventis Deutschland GmbH, Therapeutic Department Thrombosis & Angiogenesis, Frankfurt, Germany

,

Winfried März

²for the LURIC Study Group: LURIC Study gem. GmbH, Freiburg, Germany

,

Emmanuelle Cousin

³Sanofi-Aventis, Human Genetics Center, Evry, France

,

Sandrine Mace

³Sanofi-Aventis, Human Genetics Center, Evry, France

,

Jean-Francois Deleuze

³Sanofi-Aventis, Human Genetics Center, Evry, France

› Author Affiliations

Abstract

Summary

The thrombin-activatable fibrinolysis inhibitor (TAFI) is a key mediator in the regulation of endogenous fibrinolysis, down-regulating clot lysis by degrading the C-terminal lysine residues from fibrin, which are important for binding and activating plasminogen. Elevated TAFI antigen levels have been suggested to be associated with promoter variants and the Ala147Thr polymorphism; increased TAFI stability and antifibrinolytic potential instead have been associated with the Thr325Ile polymorphism. We investigated the influence of these two polymorphisms on cardiovascular and thrombotic events in patients of the Ludwig-shafen Risk and Cardiovascular Health (LURIC) study. The LURIC study is a prospective cohort study comprising more than 3,300 patients aimed at identifying biochemical and genetic markers for metabolic and cardiovascular diseases. We demonstrate that the Ile/Ile genotype at position 325 of TAFI associates with the incidence of stroke and the age at onset of first stroke in patients of the LURIC cohort. Both the incidence of stroke and the risk of a premature event are higher in TAFI Ile325Ile patients with predisposing risk factors for thrombotic events such as diabetes mellitus, myocardial infarction or hypertension, alone or in combination. In contrast, no significant association was identified for the TAFI Ala147Thr polymorphism. The robust association of the TAFI Thr325Ile polymorphism with the incidence and the age at onset of first stroke strongly suggests a key role for TAFI in the pathogenetic mechanism of stroke.

Keywords

TAFI - polymorphism - genetics - stroke

Full Text

References

References
1 Bouma BN, Marx PF, Mosnier LO. et al. Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). Thromb Res 2001; 101: 329-354.
2 Zhao L, Morser J, Bajzar L. et al. Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms. Thromb Haemost 1998; 80: 949-955.
3 Brouwers GJ, Vos HL, Leebeek FW. et al. A novel, possibly functional, single nucleotide polymorphism in the coding region of the thrombin-activatable fibrinolysis inhibitor (TAFI) gene is also associated with TAFI levels. Blood 2001; 98: 1992-1993.
4 Schneider M, Boffa M, Stewart R. et al. Two naturally occurring variants of TAFI (Thr-325 and Ile-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme. J Biol Chem 2002; 277: 1021-1030.
5 Ariëns RA, de Lange M, Snieder H. et al. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet 2002; 359: 667-671.
6 Peetz D, Victor A, Adams P. et al. Genetic and environmental influences on the fibrinolytic system: a twin study. Thromb Haemost 2004; 92: 344-351.
7 Henry M, Aubert H, Morange PE. et al. Identification of polymorphisms in the promoter and the 3’ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood 2001; 97: 2053-2058.
8 Boffa MB, Maret D, Hamill JD. et al. Effect of single nucleotide polymorphisms on expression of the gene encoding thrombin-activatable fibrinolysis inhibitor: a functional analysis. Blood 2008; 111: 183-189.
9 Guimarães AH, Bertina RM, Rijken DC. A new functional assay of thrombin activatable fibrinolysis inhibitor. J Thromb Haemost 2005; 03: 1284-1292.
10 Martini CH, Brandts A, de Bruijne EL. et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol 2006; 134: 92-94.
11 Xu CW, Wang LL, Wu XB. et al. Study on the association of thrombin activatable fibrinolysis inhibitor and the Thr325Ile and Thr147Ala polymorphisms of its encoding gene CPB2 in patients with coronary heart disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008; 25: 438-442.
12 de Bruijne EL, Darwish Murad S, de Maat MP. et al. Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis. Thromb Haemost 2007; 97: 181-185.
13 de Bruijne EL, Gils A, Guimarães AH. et al. The role of thrombin activatable fibrinolysis inhibitor (TAFI) in arterial thrombosis at young age: the ATTAC study. J Thromb Haemost 2009; 07: 919-927.
14 Heylen E, Miljic P, Willemse J. et al. Procarboxypeptidase U (TAFI) contributes to the risk of thrombosis in patients with hereditary thrombophilia. Thromb Res 2009; 124: 427-432.
15 Ladenvall C, Gils A, Jood K. et al. Thrombin activatable fibrinolysis inhibitor activation peptide shows association with all major subtypes of ischemic stroke and with TAFI gene variation. Arterioscler Thromb Vasc Biol 2007; 27: 955-962.
16 Leebeek FW, Goor MP, Guimaraes AH. et al. High functional levels of thrombinactivatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke. J Thromb Haemost 2005; 03: 2211-2218.
17 Santamaría A, Oliver A, Borrell M. et al. Risk of ischemic stroke associated with functional Thrombin-Activatable Fibinolysis Inhibitor plasma levels. Stroke 2003; 34: 2387-2391.
18 Folkeringa A, Coppens M, Veeger NJGM. et al. Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels. Thromb Haemost 2008; 100: 38-44.
19 Tregouet DA, Schnabel R, Alessi MC. et al. Activated thrombin activatable fibrinolysis inhibitor levels are associated with the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2009; 07: 49-57.
20 Winkelmann BR, März W, Boehm BO. et al. Rational and design of the LURIC study – a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2001; 02 (Suppl. 01) S1-73.
21 Mosnier LO, Meijers JC, Bouma BN. Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin. Thromb Haemost 2001; 85: 5-11.
22 Donnan GA, Fisher M, Macleod M. et al. Stroke. The Lancet 2008; 371: 1612-1623.