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.
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.
Authors: I Shimomura; T Funahashi; M Takahashi; K Maeda; K Kotani; T Nakamura; S Yamashita; M Miura; Y Fukuda; K Takemura; K Tokunaga; Y Matsuzawa Journal: Nat Med Date: 1996-07 Impact factor: 53.440
Authors: Rector Arya; John Blangero; Ken Williams; Laura Almasy; Thomas D Dyer; Robin J Leach; Peter O'Connell; Michael P Stern; Ravindranath Duggirala Journal: Diabetes Date: 2002-03 Impact factor: 9.461
Authors: K W Klinger; R Winqvist; A Riccio; P A Andreasen; R Sartorio; L S Nielsen; N Stuart; P Stanislovitis; P Watkins; R Douglas Journal: Proc Natl Acad Sci U S A Date: 1987-12 Impact factor: 11.205
Authors: H Pannekoek; H Veerman; H Lambers; P Diergaarde; C L Verweij; A J van Zonneveld; J A van Mourik Journal: EMBO J Date: 1986-10 Impact factor: 11.598
Authors: Mercedes Sotos-Prieto; Marisa Guillén; Olga Portolés; José V Sorlí; José I González; Eva M Asensio; Dolores Corella Journal: Genes Nutr Date: 2012-12-09 Impact factor: 5.523
Authors: Pushplata Prasad; Arun K Tiwari; K M Prasanna Kumar; A C Ammini; Arvind Gupta; Rajeev Gupta; B K Thelma Journal: BMC Med Genet Date: 2010-03-31 Impact factor: 2.103
Authors: Alessandra C Goulart; Kathryn M Rexrode; Suzanne Cheng; Lynda Rose; Julie E Buring; Paul M Ridker; Robert Y L Zee Journal: Am Heart J Date: 2009-08 Impact factor: 4.749