title: Promoter (4G/5G) plasminogen activator inhibitor-1 genotype in Pima Indians: relationship to plasminogen activator inhibitor-1 levels and features of the insulin resistance syndrome.
abstract: Elevated plasminogen activator inhibitor-1 may contribute to vascular disease in diabetes mellitus. Pima Indians have a low incidence of cardiovascular disease despite having a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) which in this population is not associated with elevated plasminogen activator inhibitor-1 activity. In Caucasians an insertion/deletion (4G/5G) polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene that has been related to activity levels of its protein in plasma differentially binds repressor and enhancer elements. In 265 Pima Indians (133 diabetic, 132 non-diabetic, 129 male, 136 female, male, mean age 46.6, range 34-68 years) the promoter genotype frequencies were 23.0% for 4G/4G, 49.8% for 4G/5G and 27.2% for 5G/5G compared to 35.4%, 50.8% and 13.8% respectively, (chi 2 = 15.3, 2 df, p < 0.0005) previously reported in Caucasians with NIDDM. The mean plasma activity levels in the three genotypes in the Pima Indians were 18.2, 19.1 and 18.1 U/ml, respectively. Plasminogen activator inhibitor-1 activities correlated with plasma insulin (r = 0.38, p < 0.0001), body mass index (r = 0.24, p < 0.0001), and with triglyceride level (r = 0.12, p = 0.054) but there was no relationship between promotor genotype and activity. A steeper regression slope between plasminogen activator inhibitor-1 activity and triglycerides has been observed in Caucasians with the 4G/4G genotype as compared to Caucasians with the other genotypes. This was not found in the Pima population which may indicate a functional difference in this gene associated with reduced cardiovascular risk and may be involved in the lack of association of plasminogen activator inhibitor-1 levels with NIDDM in Pima Indians.
authors.affiliation: Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: McCormack
authors.forename: D K
authors.initials: DK
authors.lastname: Nagi
authors.forename: M H
authors.initials: MH
authors.lastname: Stickland
authors.forename: M W
authors.initials: MW
authors.lastname: Mansfield
authors.forename: V
authors.initials: V
authors.lastname: Mohamed-Ali
authors.forename: J S
authors.initials: JS
authors.lastname: Yudkin
authors.forename: W C
authors.initials: WC
authors.lastname: Knowler
authors.forename: P J
authors.initials: PJ
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D001130:Arizona; D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D013577:Syndrome
chemical_list: D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1