title: FXIII-A Leu34 genetic variant in premature coronary artery disease: a genotype--phenotype case control study.
abstract: 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-¹ x 10(-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-¹ x 10(-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.
authors.affiliation: Institut de Cardiologie, INSERM UMRS 937, Pitié-Salpêtrière Hospital, AP-HP, Université Paris 6, Paris, France.
authors.forename: Johanne
authors.initials: J
authors.lastname: Silvain
authors.forename: Ana
authors.initials: A
authors.lastname: Pena
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vignalou
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Sophie
authors.initials: S
authors.lastname: Galier
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cayla
authors.forename: Anne
authors.initials: A
authors.lastname: Bellemain-Appaix
authors.forename: Olivier
authors.initials: O
authors.lastname: Barthélémy
authors.forename: Farzin
authors.initials: F
authors.lastname: Beygui
authors.forename: Claire
authors.initials: C
authors.lastname: Bal-dit-Sollier
authors.forename: Ludovic
authors.initials: L
authors.lastname: Drouet
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.forename: Jean-Phillippe
authors.initials: JP
authors.lastname: Collet
mesh_terms: D000328:Adult; D000367:Age Factors; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D003328:Coronary Thrombosis; D004252:DNA Mutational Analysis; D005176:Factor XIII / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006439:Hemodynamics; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D009203:Myocardial Infarction; D011110:Polymorphism, Genetic; D012008:Recurrence; D016019:Survival Analysis
chemical_list: D005176:Factor XIII; D007930:Leucine