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Thromb Haemost 2011; 106(03): 511-520
DOI: 10.1160/TH11-01-0027
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

FXIII-A Leu34 genetic variant in premature coronary artery disease: A genotype – phenotype case control study

Johanne Silvain
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Ana Pena
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Jean-Baptiste Vignalou
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Jean-Sébastien Hulot
2   Pharmacogenomic unit, INSERM UMRS 621, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Sophie Galier
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Guillaume Cayla
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Anne Bellemain-Appaix
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Olivier Barthélémy
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Farzin Beygui
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Claire Bal-dit-Sollier
3   Institut des Vaisseaux et du Sang, CHU – Lariboisière – Paris, France
,
Ludovic Drouet
3   Institut des Vaisseaux et du Sang, CHU – Lariboisière – Paris, France
,
John W. Weisel
4   Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
,
Gilles Montalescot
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
,
Jean-Phillippe Collet
1   Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France
› Institutsangaben Financial support: This study was supported by the French Federation for Medical Research (FRM) and partially by NIH HL30954 and HL090774.
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Publikationsverlauf

Received: 18. Januar 2011

Accepted after major revision: 22. Mai 2011

Publikationsdatum:
24. November 2017 (online)

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Summary

The FXIII-A Leu34 genetic variant increases and accelerates fibrin stabilisation; however, its association with premature coronary artery disease (CAD) and thrombotic events remains controversial. FXIII Val34Leu genotype was determined in 242 young individuals (<45 years old) who survived a myocardial infarction (MI) and 242 healthy controls matched for age and gender. We evaluated its effect on longterm clinical outcome defined as a composite of cardiovascular death, recurrent MI and urgent revascularisation. In addition, fibrin clot stiffness (elastic modulus or EM) and response to rt-PA-mediated fibrinolysis (fibrinolysis rate) were measured ex vivo using the Hemodyne analyser and confocal microscopy as surrogate endpoint. FXIII-A Leu34 genetic variant was not associated with premature CAD (adj. odds ratio 0.83 [0.49–1.4]) nor did it influence clinical outcome in patients, during a median follow-up of 6.3 (± 2.4) years. Patients produced stiffer fibrin clots (median [IQR] EM =20.3 [14.9–28.1] vs. 12.8 [9.6–17.1] kdynes/ cm2; p<0.0001) and displayed reduced response to fibrinolysis with lower fibrinolysis rate (6.7 [3.4–11.0] vs. 9.0 [5.0–16.7] sec-1x10−4; p<0.0001) than healthy controls. Carriage of factor XIII-A Leu34 led to a stepwise decrease in fibrinolysis rate with a significant gene–dose-effect in patients (7.7 [4.1–12.2] vs. 4.8 [3.0–8.5] vs. 4.3 [2.4–8.1] sec-1x10−4, for wild-type, heterozygous and homozygous, p for trend =0.003) and a non-significant trend in controls (p=0.01). In conclusion, FXIII-A Leu34 is a polymorphism which provides a strong resistance to fibrinolysis with a gene-dose effect, but does not relate to premature CAD or to recurrent coronary events in this study.

Keywords

Factor XIII Val34Leu - pharmacogenetic - fibrinolysis - thrombosis - coronary disease - fibrin structure
 

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