title: A common 4G allele in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency.
abstract: Reduced fibrinolytic capacity due to increased plasminogen activator inhibitor-1 (PAI-1) activity in plasma is a common finding in patients with coronary heart disease or venous thromboembolism, although its clinical significance is debated. Recently, a dimorphism in the PAI-1 promoter (4G-5G) has been reported and homozygosity for the 4G allele is associated with increased transcription and higher PAI-1 levels. Homozygous 4G genotype has been suggested to be a risk factor for myocardial infarction. In the present study, the 4G-5G dimorphism was determined in 349 individuals from 21 thrombophilic families with hereditary protein S deficiency and in 140 unrelated healthy controls. Among the 143 protein S deficient individuals, there was no relationship between deep or superficial venous thrombosis and the PAI-1 dimorphism. However, 26% (12/46) of individuals having protein S deficiency combined with homozygosity for the 4G allele had suffered pulmonary embolism as compared to 7% (7/97) of protein S deficient individuals carrying at least one 5G allele (p = 0.0019). In protein S deficient individuals, arterial thrombosis was found to be associated with smoking and 4G homozygosity. No association was found between the PAI-1 dimorphism and arterial or venous thromboembolism in family members without protein S deficiency. In conclusion, the PAI-1 genotype affects the phenotypic expression of thrombophilia in protein S deficient individuals.
authors.affiliation: Department of Clinical Chemistry, Malmö University Hospital, Lund University, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Zöller
authors.forename: P
authors.initials: P
authors.lastname: García de Frutos
authors.forename: B
authors.initials: B
authors.lastname: Dahlbäck
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D004252:DNA Mutational Analysis; D004843:Epistasis, Genetic; D005260:Female; D005342:Fibrinolysis / Q000235:genetics; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018455:Protein S Deficiency / Q000150:complications / Q000235:genetics*; D011655:Pulmonary Embolism / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D012307:Risk Factors; D019851:Thrombophilia / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D013924:Thrombophlebitis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D013927:Thrombosis / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics
chemical_list: D017395:Plasminogen Activator Inhibitor 1