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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH11-01-0027
Issue: 2011: 106/3 (Sep) pp. 389–565
Pages: 511-520

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

J. Silvain (1), A. Pena (1), J.-B. Vignalou (1), J.-S. Hulot (2), S. Galier (1), G. Cayla (1), A. Bellemain-Appaix (1), O. Barthélémy (1), F. Beygui (1), C. Bal-dit-Sollier (3), L. Drouet (3), J. W. Weisel (4), G. Montalescot (1), J.-P. Collet (1)

(1) Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France; (2) Pharmacogenomic unit, INSERM UMRS 621, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6, Paris, France; (3) Institut des Vaisseaux et du Sang, CHU – Lariboisière – Paris, France; (4) Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

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 long-term 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

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

DOI

http://dx.doi.org/10.1160/TH11-01-0027

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