The plasminogen activator inhibitor-1 (PAI-1) promoter haplotype is related to PAI-1 plasma concentrations in lean individuals

BACKGROUND: Elevated plasminogen activator inhibitor-1 (PAI-1) concentrations are associated with cardiovascular diseases. PAI-1 antigen levels are influenced by environmental factors such as body mass index (BMI), and by genetic factors. The PAI-1 promoter of the PAI-1 gene contains two common polymorphisms (-844A/G and -675(4G/5G)) and the 4G allele of the -675(4G/5G) variation has been associated with elevated PAI-1 concentrations and on some occasions with an increased risk of cardiovascular disease. OBJECTIVES: The aim of our study was to investigate the effect of the PAI-1 promoter haplotype on PAI-1 concentrations and to determine the role of BMI. METHODS: The association between the PAI-1 promoter haplotype and PAI-1 antigen levels was investigated in two independent populations, each including 600 healthy Caucasians. Furthermore, to assess the effect of the PAI-1 promoter haplotype on PAI-1 promoter activity, in vitro reporter gene assays were performed in HepG2 and BAEC cells. RESULTS: We observed significantly higher PAI-1 concentrations in A-4G homozygotes than in G-5G carriers in lean subjects (BMI in the lowest quartile). In these lean subjects, the PAI-1 concentrations in A-4G/G-5G heterozygotes were reduced to 60-75%, and the concentrations in G-5G homozygotes to 45-55%, compared to the PAI-1 concentrations of A-4G homozygotes (p < 0.01). PAI-1 concentrations increased approximately four-fold from the lowest to the highest BMI quartile (p < 0.01). The reporter gene assays did not support a direct effect of the PAI-1 promoter haplotype on promoter activity in HepG2 or BEAC cells. CONCLUSIONS: Our study suggests that the PAI-1 promoter haplotype and BMI affect PAI-1 concentrations and that BMI is a stronger determinant than PAI-1 promoter variation.