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


CONCLUSIONS
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.
Rossaak
J I
JI
Department of Surgery, Dunedin School of Medicine, University of Otago, New Zealand.
Van Rij
A M
AM
Jones
G T
GT
Harris
E L
EL
D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics
D017395:Plasminogen Activator Inhibitor 1