title: Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.
abstract: Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sundquist
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Svensson
authors.forename: Jan
authors.initials: J
authors.lastname: Sundquist
authors.forename: Anna
authors.initials: A
authors.lastname: Hedelius
authors.forename: Sara
authors.initials: S
authors.lastname: Larsson Lönn
authors.forename: Bengt
authors.initials: B
authors.lastname: Zöller
authors.affiliation: Ashfaque A. Memon, Center for Primary Health Care Research, Wallenberg Laboratory, 6th floor, Inga Marie Nilssons gata 53, Skåne University Hospital, S-205 02 Malmö, Sweden, Tel.: +46 40331465, Fax: +46 40391370, E-mail: ashfaque.memon@med.lu.se.
authors.forename: Ashfaque A
authors.initials: AA
authors.lastname: Memon
mesh_terms: D020016:Activated Protein C Resistance / Q000150:complications / Q000235:genetics; D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000627:therapeutic use; D018572:Disease-Free Survival; D005165:Factor V / Q000235:genetics*; D005260:Female; D005342:Fibrinolysis / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011516:Prothrombin / Q000235:genetics*; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000235:genetics*; D012008:Recurrence; D012306:Risk; D013548:Sweden / Q000453:epidemiology; D019851:Thrombophilia / Q000188:drug therapy / Q000235:genetics*; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin
keywords: Fibrinolysis; PAI-1 polymorphism; plasminogen; recurrence; venous thromboembolism