Diabetic Retinopathy, Promoter (4G/5G) Polymorphism of PAI-1 Gene, and PAI-1 Activity in Pima Indians With Type 2 Diabetes

Nagi, Dinesh; McCormack, L. J.; Mohamed‐Ali, Vidya; Yudkin, John; Knowler, William C.; Grant, Peter J.

doi:10.2337/diacare.20.8.1304

Cited by 53 publications

(31 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transforming growth factor-␤ gene has shown evidence of association only with proliferative retinopathy (28). A previous candidate gene study in the Pimas reported a modest association between retinopathy (as assessed by fundoscopy) and a polymorphism in the promoter region of the plasminogen activator inhibitor 1 gene on chromosome 7 (29). None of these genes, however, map to the area of linkage identified in the current study.…”

Section: Discussioncontrasting

confidence: 50%

Genome-Wide Linkage Analyses to Identify Loci for Diabetic Retinopathy

et al. 2007

View full text Add to dashboard Cite

Hyperglycemia and long duration of diabetes are widely recognized risk factors for diabetic retinopathy, but inherited susceptibility may also play a role because retinopathy aggregates in families. A genome-wide linkage analysis was conducted in 211 sibships in which >2 siblings had diabetes and retinal photographs were available from a longitudinal study. These sibships were a subset of 322 sibships who had participated in a previous linkage study of diabetes and related traits; they comprised 607 diabetic individuals in 725 sibpairs. Retinal photographs were graded for presence and severity of diabetic retinopathy according to a modification of the Airlie House classification system. The grade for the worse eye was adjusted for age, sex, and diabetes duration and analyzed as a quantitative trait. Heritability of diabetic retinopathy in this group was 18% (95% CI 2-36). A genome-wide linkage analysis using variance components modeling found evidence of linkage on chromosome 1p. Using single-point analysis, the peak logarithm of odds (LOD) was 3.1 for marker D1S3669 (34.2 cM), whereas with multipoint analysis the peak LOD was 2.58 at 35 cM. No other areas of suggestive linkage were found. We propose that an area on chromosome 1 may harbor a gene or genes conferring susceptibility to diabetic retinopathy.

show abstract

Section: Discussioncontrasting

confidence: 50%

Genome-Wide Linkage Analyses to Identify Loci for Diabetic Retinopathy

et al. 2007

View full text Add to dashboard Cite

show abstract

“…In women, the 4 G-allele predicted a slightly increased risk of myocardial infarction (Leander et al 2003). In contrast, the 5 G/5 Ggenotype of PAI-1 has been found associated with myocardial infarction in women (Yamada et al 2002) whereas in 171 type 2 diabetic Pima Indians, subjects with the 4 G/4 G and the 4 G/5 G genotype had a higher prevalence of retinopathy (Nagi et al 1997). In 519 Caucasian diabetic patients (192 with type 1 and 327 with type 2 diabetes) (Mansfield et al 1995b) and, in another study, in 204 type 2 diabetic patients no association between PAI-1 polymorphism and the prevalence of retinopathy could be identified (GlobocnikPetrovic et al 2003).…”

Section: Introductionmentioning

confidence: 82%

Plasminogen activator inhibitor-1 promoter activity in adipocytes is not influenced by the 4 G/5 G promoter polymorphism and is regulated by a USF-1/2 binding site immediately preceding the polymorphic region

Zietz

Drobnik

Herfarth

et al. 2004

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Plasminogen activator inhibitor-1 (PAI-1) levels were found to be associated with obesity indicating that adipocytes influence PAI-1 plasma levels. In addition, the 4 G/5 G promoter polymorphism of the PAI-1 gene may modulate PAI-1 transcription. We investigated the transcriptional regulation of the human PAI-1 gene in adipocytes and analyzed the genetic contribution of the 4 G/5 G polymorphism. The PAI-1 promoter was analyzed using electrophoretic mobility shift assays (EMSAs) and luciferase reporter gene assays. A putative binding site for the upstream stimulatory factor-1/2 (USF-1/2) at the polymorphic region of the PAI-1 promoter was identified.

show abstract

“…Previous studies suggested an association between PAI-1 −844 A>G and the 4G/5G polymorphisms and vascular complications in non-insulin-dependent diabetic individuals [35,36]. Moreover, fasting insulin levels, triglycerides and BMI have also been associated with the 4G/5G in subjects with hyperlipidaemia and premature coronary disease or non-insulin-dependent diabetes in Caucasians [24,37,38], but not in all tested populations [39,40].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

View full text Add to dashboard Cite

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 −844A>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 andp=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; −844A>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. [Diabetologia (2003[Diabetologia ( ) 46:1284[Diabetologia ( -1290 Keywords PAI-1, obesity, metabolic syndrome, CHD, fasting glucose, insulin, triglycerides, HDL, Type 2 diabetes mellitus.

show abstract

Diabetic Retinopathy, Promoter (4G/5G) Polymorphism of PAI-1 Gene, and PAI-1 Activity in Pima Indians With Type 2 Diabetes

Cited by 53 publications

References 25 publications

Genome-Wide Linkage Analyses to Identify Loci for Diabetic Retinopathy

Genome-Wide Linkage Analyses to Identify Loci for Diabetic Retinopathy

Plasminogen activator inhibitor-1 promoter activity in adipocytes is not influenced by the 4 G/5 G promoter polymorphism and is regulated by a USF-1/2 binding site immediately preceding the polymorphic region

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

Contact Info

Product

Resources

About