The plasminogen activator inhibitor-1 (PAI-1) promoter haplotype is related to PAI-1 plasma concentrations in lean individuals
article
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. © 2005 Elsevier Ireland Ltd. All rights reserved. Chemicals / CAS: adenine, 22177-51-1, 2922-28-3, 73-24-5; guanine, 69257-39-2, 73-40-5; plasminogen activator inhibitor 1, 140208-23-7; Plasminogen Activator Inhibitor 1
Topics
Biomedical ResearchBMIGenetic variationPAI-1Promoter haplotypesadenineguanineplasminogen activator inhibitor 1cell straincell strain HepG2comparative studycontrolled studygenetic associationgenetic polymorphismgenetic variabilityhaplotypeheterozygosityhomozygosityhuman cellin vitro studylean body weightmajor clinical studymedical assessmentpriority journalpromoter regionprotein blood levelreporter geneAdultAgedBody Mass IndexBody WeightCarcinoma, HepatocellularCell Line, TumorFemaleGenes, ReporterHaplotypesHumansLiver NeoplasmsMaleMiddle AgedPlasminogen Activator Inhibitor 1Promoter Regions (Genetics)Variation (Genetics)
TNO Identifier
238636
ISSN
00219150
Source
Atherosclerosis, 181(2), pp. 275-284.
Pages
275-284
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