Rare genotypes of protein Z gene are a risk factor for premature myocardial infarction but not protein Z plasma level

Véronique Le Cam-Duchez; Claudine Soria; Claire Bal dit Sollier; Jeanne-Yvonne Borg; Mathieu Coudert; Gilles Montalescot; Gaétan Esposito; Ludovic Drouet; Jean-Philippe Collet

doi:10.1160/TH09-01-0007

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 102(01): 131-136
DOI: 10.1160/TH09-01-0007

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Rare genotypes of protein Z gene are a risk factor for premature myocardial infarction but not protein Z plasma level

Authors

Véronique Le Cam-Duchez

¹Unit of Vascular Haemostasis, Rouen University Hospital, Rouen, France

²EA3829 (Research Group MERCI), Institute for Biomedical Research, University of Rouen, Rouen, France
Claudine Soria

²EA3829 (Research Group MERCI), Institute for Biomedical Research, University of Rouen, Rouen, France

³Haematology Laboratory, Lariboisière University Hospital, Paris, France
Claire Bal dit Sollier

³Haematology Laboratory, Lariboisière University Hospital, Paris, France
Jeanne-Yvonne Borg

¹Unit of Vascular Haemostasis, Rouen University Hospital, Rouen, France

²EA3829 (Research Group MERCI), Institute for Biomedical Research, University of Rouen, Rouen, France
Mathieu Coudert

⁴APHP, Pitié-Salpêtrière Charles-Foix Clinical Research Unit, Paris, France

⁵UPMC Univ. Paris 06, EA 3974, Modelling in Clinical Research, Paris, France
Gilles Montalescot

⁶Department of Cardiology, Pitié-Salpêtrière University Hospital, Paris, France
Gaétan Esposito

³Haematology Laboratory, Lariboisière University Hospital, Paris, France
Ludovic Drouet

³Haematology Laboratory, Lariboisière University Hospital, Paris, France
Jean-Philippe Collet

⁶Department of Cardiology, Pitié-Salpêtrière University Hospital, Paris, France

Abstract

Summary

Protein Z (PZ) is the cofactor of PZ dependent inhibitor (ZPI) that inhibits activated coagulation factor X. PZ was expected to play a role in coronary artery disease (CAD) but with inconsistent clinical findings. We therefore evaluated whether PZ plasma level and/or three genetic variants encoding for low PZ plasma level were associated with premature CAD in stable young post-myocardial infarction (MI) patients. PZ plasma level and three polymorphisms A-13G, G-103A and G79A were determined in 176 young stable post-MI patients and in 176 sex- and age-matched controls (FITE-NAT population). Moreover the genotypes, resulting from the combination of the three polymorphisms (A-13G/G-103A/G79A), were studied. PZ plasma level and the number of patients disclosing a PZ deficiency did not differ between post-MI patients and controls. The presence of the mutated allele for each polymorphism was associated with a significantly reduced level of PZ. The A-13G polymorphism was associated with premature CAD only in univariate analysis. Whereas, the presence of rare genotypes of PZ gene was an independent risk factor for premature CAD. In conclusion, PZ plasma level is not a key player in the pathophysiology of premature coronary artery disease. But, rare genotypes of PZ gene were found to be associated with premature CAD.

Keywords

Genetics - myocardial infarction - polymorphism - protein Z - young adults

Full Text

References

References
1 Broze Jr. GJ. Protein Z-dependent regulation of coagulation. Thromb Haemost 2001; 86: 8-13.
2 Tabatabai A, Fiehler R, Broze Jr. GJ. Protein Z circulates in plasma in a complex with protein Z-dependent protease inhibitor. Thromb Haemost 2001; 85: 655-660.
3 Kemkes-Matthes B, Nees M, Kuhnel G. et al. Protein Z influences the prothrombotic phenotype in Factor V Leiden patients. Thromb Res 2002; 106: 183-185.
4 Greten J, Kreis I, Liliensiek B. et al. Localisation of protein Z in vascular lesions of patients with atherosclerosis. Vasa 1998; 27: 144-148.
5 Kobelt K, Biasiutti FD, Mattle HP. et al. Protein Z in ischaemic stroke. Br J Haematol 2001; 114: 169-173.
6 Vasse M, Guegan-Massardier E, Borg JY, Woimant F, Soria C. Frequency of protein Z deficiency in patients with ischaemic stroke. Lancet 2001; 357: 933-934.
7 Heeb MJ, Paganini-Hill A, Griffin JH, Fisher M. Low protein Z levels and risk of ischemic stroke: differences by diabetic status and gender. Blood Cells Mol Dis 2002; 29: 139-144.
8 Fedi S, Sofi F, Brogi D. et al. Low protein Z plasma levels are independently associated with acute coronary syndromes. Thromb Haemost 2003; 90: 1173-1178.
9 Morange PE, Juhan-Vague I. Protein Z plasma levels are not associated with the risk of coronary heart disease: the PRIME Study. J Thromb Haemost 2004; 02: 2050-2051.
10 Sofi F, Cesari F, Pratesi G. et al. Low protein Z levels in patients with peripheral arterial disease. Thromb Haemost 2007; 98: 1114-1117.
11 Sofi F, Cesari F, Marcucci R. et al. Protein Z levels and prognosis in patients with acute coronary syndromes. Clin Chem Lab Med 2006; 44: 1098-1102.
12 Vasse M, Denoyelle C, Legrand E, Vannier JP, Soria C. Weak regulation of protein Z biosynthesis by inflammatory cytokines. Thromb Haemost 2002; 87: 350-351.
13 Staton J, Sayer M, Hankey GJ. et al. Protein Z gene polymorphisms, protein Z concentrations, and ischemic stroke. Stroke 2005; 36: 1123-1127.
14 Santacroce R, Cappucci F, Di Perna P, Sessa F, Margaglione M. Protein Z gene polymorphisms are associated with protein Z plasma levels. J Thromb Haemost 2004; 02: 1197-1199.
15 Rice GI, Futers TS, Grant PJ. Identification of novel polymorphisms within the protein Z gene, haplotype distribution and linkage analysis. Thromb Haemost 2001; 85: 1123-1124.
16 Cesari F, Fatini C, Sticchi E. et al. Protein Z gene polymorphisms (intron F 79 G>A; -13 A>G) are not associated with acute coronary syndromes. Thromb Haemost 2006; 96: 98-99.
17 Le Cam-Duchez V, Barbay V, Bal dit, Sollier C. et al. Haplotypic or genotypic combinations of three PZ polymorphisms influence Protein Z plasma level. Thromb Haemost 2009; 101: 212-214.
18 Le Cam-Duchez V, Bagan-Triquenot A, Barbay V. et al. The G79A polymorphism of protein Z gene is an independant risk factor for cerebral venous thrombosis. J Neurol 2008; 255: 1521-1525.
19 Montalescot G, Collet JP, Tanguy ML. et al. Anti- Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 2004; 110: 392-398.
20 Mazoyer E, Ripoll L, Gueguen R. et al. Environmental and genetic influences on fibrinogen level differently evidenced according to the technique of fibrinogen measurement: FITE NAT multicenter study. Thromb Haemost. 2001 Suppl: Abstract 2197.
21 Lichy C, Kropp S, Dong-Si T. et al. A common polymorphism of the protein Z gene is associated with protein Z plasma levels and with risk of cerebral ischemia in the young. Stroke 2004; 35: 40-45.
22 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
23 Poort SR, Rosendaal FR, Reitsma PH. et al. 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. Blood 1996; 88: 3698-3703.
24 Ardissino D, Mannucci PM, Merlini PA. et al. Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood 1999; 94: 46-51.
25 Barbash GI, White HD, Modan M. et al. Acute myocardial infarction in the young--the role of smoking. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial. Eur Heart J 1995; 16: 313-316.
26 Fournier JA, Sanchez-Gonzalez A, Quero J. et al. Normal angiogram after myocardial infarction in young patients: a prospective clinical-angiographic and long-term follow-up study. Int J Cardiol 1997; 60: 281-287.
27 Teo KK, Ounpuu S, Hawken S. et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet 2006; 368: 647-658.
28 Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-952.
29 Middendorf K, Gohring P, Huehns TY. et al. Prevalence of resistance against activated protein C resulting from factor V Leiden is significantly increased in myocardial infarction: investigation of 507 patients with myocardial infarction. Am Heart J 2004; 147: 897-904.
30 Segev A, Ellis MH, Segev F. et al. High prevalence of thrombophilia among young patients with myocardial infarction and few conventional risk factors. Int J Cardiol 2005; 98: 421-424.
31 Atherosclerosis tavbisg. No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation 2003; 107: 1117-1122.
32 Boekholdt SM, Kramer MH. Arterial thrombosis and the role of thrombophilia. Semin Thromb Hemost 2007; 33: 588-596.
33 Linnemann B, Schindewolf M, Zgouras D. et al. Are patients with thrombophilia and previous venous thromboembolism at higher risk to arterial thrombosis?. Thromb Res 2008; 121: 743-750.
34 Zee RY, Cook NR, Cheng S. et al. Multi-locus candidate gene polymorphisms and risk of myocardial infarction: a population-based, prospective genetic analysis. J Thromb Haemost 2006; 04: 341-348.
35 Sofi F, Lari B, Rogolino A, Marcucci R, Pratesi G, Dorigo W. et al. Thrombophilic risk factors for symptomatic peripheral arterial disease. J Vasc Surg 2005; 41: 255-260.
36 Vasse M. Protein Z, a protein seeking a pathology. Thromb Haemost 2008; 100: 548-556.
37 Ndonwi M, Lu L, Tu Y. et al. Functional analysis of protein Z (Arg255His) and protein Z-dependent protease inhibitor (Lys25Arg and Ser40Gly) polymorphisms. Br J Haematol 2008; 143: 298-300.