PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Diabetologia Année : 2003

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

Résumé

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 beta-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.

Dates et versions

hal-00174577 , version 1 (24-09-2007)

Identifiants

Citer

C. Lopes, C. Dina, E. Durand, P. Froguel. PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population.. Diabetologia, 2003, 46 (9), pp.1284-90. ⟨10.1007/s00125-003-1170-0⟩. ⟨hal-00174577⟩

Collections

METEO RIIP CNRS
93 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More