Association of the 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor-1 with abdominal aortic aneurysms

• Published in: Journal of vascular surgery 2000-05, Vol.31 (5), p.1026-1032
• Main Authors: Rossaak, Jeremy I., van Rij, André M., Jones, Gregory T., Harris, Eugenie L.
• Format: Article
• Language: English
• Subjects: Aged; Aortic Aneurysm, Abdominal - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Case-Control Studies; Diseases of the aorta; Female; Genetic Variation; Genotype; Humans; Male; Medical sciences; Plasminogen Activator Inhibitor 1 - genetics; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic - genetics
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1067/mva.2000.104589

Purpose: A familial component has previously been identified in 11% to 20% of patients with abdominal aortic aneurysms (AAAs). The genetic basis of familial AAA remains elusive, however. Matrix metalloproteinases have been implicated in aneurysm development; and plasmin, a serine protease, activates metalloproteinases. Plasminogen activator inhibitor-1 (PAI-1) regulates plasmin activation through the tissue plasminogen activators. A polymorphism within the promoter area of PAI-1 has been described that modifies PAI-1 expression and consequently plasminogen activation. The 4G homozygous variant is associated with increased PAI-1 expression and consequently reduced plasmin activity and therefore may be selected against in-familial AAA. The purpose of this study was to investigate the incidence of the 4G/5G insertion/deletion polymorphism in the promoter area of the PAI-1 gene in a population with AAA. Methods: Patients seen at a tertiary referral center for repair of abdominal aortic aneurysms were recruited. DNA was extracted from blood. Primers were designed to amplify a 99 (5G)-base pair (bp) and a 98 (4G)-bp fragment bracketing the polymorphism. The 5′ primer was mutated to allow a restriction endonuclease to cleave the 5G polymorphism into a 77-bp and a 22-bp fragment. Samples were run on agarose gels and stained with ethidium bromide. Results: One hundred ninety patients with AAAs, including 39 patients with strong family histories and 163 controls were examined. The frequency of the 4G:5G alleles in the AAA population and in the control population was 0.6:0.4. However, 26% of patients with familial AAA were homozygous 5G compared with 13% of the control population. The 4G-allele frequency was 0.47 in the familial AAAs, compared with 0.62 in the nonfamilial patients (P =.02) and 0.61 in the control population (P =.03). Conclusion: The selection against the 4G4G genotype in the familial AAA population may indicate a role for PAI in the development of AAA in this population. (J Vasc Surg 2000;31:1026-32.)