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.


OBJECTIVE
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.
Verschuur
Maartje
M
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
Jellema
Annemarie
A
Bladbjerg
Else M
EM
M Feskens
Edith J
EJ
Mensink
Ronald P
RP
Møller
Lars
L
Vos
Hans L
HL
de Maat
Moniek P M
MP
D000328:Adult; D000368:Aged; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D005260:Female; D017930:Genes, Reporter; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
D017395:Plasminogen Activator Inhibitor 1