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Diabetologia
Published in: Diabetologia 9/2003

01-09-2003 | Article

PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population

Authors: C. Lopes, C. Dina, E. Durand, Dr. P. Froguel

Published in: Diabetologia | Issue 9/2003

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Abstract

Aim/hypothesis

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 β-sheet structure, could influence conformation of these two structures.

Conclusions/interpretation

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.
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Metadata
Title
PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population
Authors
C. Lopes
C. Dina
E. Durand
Dr. P. Froguel
Publication date
01-09-2003
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2003
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-003-1170-0

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