title: The alpha-2-antiplasmin Arg407Lys polymorphism is associated with abdominal aortic aneurysm.
abstract: Abdominal Aortic Aneurysm (AAA) involves dilatation of the abdominal aorta, with a natural history of expansion and eventual rupture. We have previously shown that AAA patients form denser clots with smaller pores, which are more resistant to fibrinolysis. The aim of this study was to use functional polymorphisms of the fibrinolytic system to identify how changes to proteins involved in fibrinolysis may play a role in the development of AAA.
  
  
  
  Caucasian subjects ≥ 55 years (602 AAA patients and 490 matched controls) were genotyped for four polymorphisms (α-2-antiplasmin α2AP Arg6Trp and Arg407Lys, Thrombin-activatable fibrinolysis inhibitor TAFI Thr325Ile and tissue plasminogen activator tPA 7351C→T). DNA was extracted from blood, and genotype identified using real time PCR. Fibrin clot structure was analysed by permeation and turbidity in a subset of patients and controls.
  
  
  
  Genotypes across the study population were in Hardy-Weinberg Equilibrium. The two α2AP polymorphisms, Arg6Trp and Arg407Lys were in linkage disequilibrium (P<0.0001), and possession of a 407Lys allele negatively associated with AAA (odds ratio 0.833, CI95 0.7-0.991, P=0.040). The TAFI Thr325Ile and the tPA 7351C→T polymorphisms were not associated with AAA. The α2AP 407Lys allele was not associated with in-vitro fibrinolysis times in plasma from patients with AAA.
  
  
  
  Possession of the α2AP 407Lys allele was negatively associated with AAA, and thus changes in α2AP may affect aneurysm growth and development. These data indicate that the regulation of plasmin activity (through binding to α2AP), rather than plasmin generation (TAFI, tPA), may play a role in AAA.
authors: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre; University of Leeds, UK; Leeds Vascular Institute, The General Infirmary at Leeds, Leeds, UK.
authors: Katherine I
authors: KI
authors: Bridge
authors: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre; University of Leeds, UK.
authors: Fraser
authors: F
authors: Macrae
authors: Leeds Vascular Institute, The General Infirmary at Leeds, Leeds, UK.
authors: Marc A
authors: MA
authors: Bailey
authors: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre; University of Leeds, UK; Leeds Vascular Institute, The General Infirmary at Leeds, Leeds, UK.
authors: Anne
authors: A
authors: Johnson
authors: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre; University of Leeds, UK.
authors: Helen
authors: H
authors: Philippou
authors: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre; University of Leeds, UK; Leeds Vascular Institute, The General Infirmary at Leeds, Leeds, UK.
authors: D Julian A
authors: DJ
authors: Scott
authors: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds institute for Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre; University of Leeds, UK. Electronic address: r.a.s.ariens@leeds.ac.uk.
authors: Robert A S
authors: RA
authors: Ariens
mesh_terms: D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000097:blood / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004739:England; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D044465:White People / Q000235:genetics; D000979:alpha-2-Antiplasmin / Q000235:genetics*
chemical_list: C534949:SERPINF2 protein, human; D000979:alpha-2-Antiplasmin; D005337:Fibrin
keywords: Abdominal Aortic Aneurysm; Alpha-2-antiplasmin; Aneurysm; Fibrinolysis; Genetic Polymorphism