PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population.
OBJECTIVE
Plasminogen activator inhibitor-1 (PAI-1) is a main regulator of the endogenous fibrinolytic system and modulates the thrombosis progression. We analyzed genetic contributions of PAI-1 mutations to the metabolic syndrome and to its complications.


METHODS
PAI-1 promoter and coding sequences were screened for mutations. Genotypes were determined for 1067 unrelated individuals of a French Caucasian cohort, selected for diabetes and obesity. Association between PAI-1 polymorphisms and phenotypes related to metabolic syndrome were statistically studied.


RESULTS
There were five variants identified: two common polymorphisms, -765 4G/5G and -844 A>G, in the promoter, and three new non-synonymous SNPs, Ala15Thr, Val17Ile and Asn195Ile. In obese non-diabetic subjects, the two promoter polymorphisms were associated with higher fasting glucose concentrations (p=0.006 and p=0.0004, for -765 4G/5G and -844 A>G, respectively) and insulin (p=0.05 and p=0.008, for -765 4G/5G and -844 A>G, respectively). Moreover, the -844 A>G SNP was associated with lower triglyceride (p=0.002) and higher HDL cholesterol concentrations (p=0.02) in lean subjects. In addition, the two promoter and Ala15Thr polymorphisms showed a trend towards association with CHD in diabetic subjects (-765 4G/5G: 0.56/0.51, p=0.05; -844 A>G: 0.63/0.57, p=0.02; Ala15Thr: 0.91/0.88, p=0.04). The SNPs Ala15Thr, located in the PAI-1 signal peptide, and rare the Asn195Ile, located in a beta-sheet structure, could influence conformation of these two structures.


CONCLUSIONS
Our results support the hypothesis that PAI-1 polymorphisms probably interact with known environmental risk factors (chronic hyperglycaemia, obesity, etc.) to induce a more severe insulin-resistant metabolic profile in overweight subjects, and to further increase risk for CHD in diabetic subjects.
Lopes
C
C
Hammersmith Genome Centre, Imperial College, London, UK.
Dina
C
C
Durand
E
E
Froguel
P
P
D015992:Body Mass Index; D016022:Case-Control Studies; D015331:Cohort Studies; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005602:France; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity; D010375:Pedigree; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014280:Triglycerides / Q000097:blood; D044465:White People / Q000235:genetics
D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides