Diabetic retinopathy, PAI-1 4G/5G and −844G/A polymorphisms, and changes in circulating PAI-1 levels in Tunisian type 2 diabetes patients

Abstract

Aim The association of altered plasminogen activator inhibitor (PAI)-1 levels and PAI-1 polymorphisms (4G/5G and −844G/A) with diabetic retinopathy (DR) was investigated in 856 type 2 diabetes (T2D) patients, of whom 383 presented with (DR group), and 473 presented without (DWR group), retinopathy. Methods PAI-1 4G/5G and −844G/A genotyping were done by PCR-RFLP, and PAI-1 levels were measured by ELISA testing. Results The genotype distribution of 4G/5G and −844G/A polymorphisms did not deviate from the Hardy-Weinberg equilibrium model among healthy subjects. Higher frequencies of the 4G/4G genotype, and lower frequencies of the −844A allele, −844G/A and −844A/A genotypes, were seen in DR patients, conferring disease susceptibility and protection, respectively. While PAI-1 levels were significantly elevated in the 4G/4G compared with other PAI-1 genotypes, significant differences in PAI-1 levels between DR and DWR patients were seen in the 4G/−844A, 4G/−844G and 5G/−844A haplotype carriers among DR patients. However, comparable distributions of 4G/5G and −844G/A alleles, genotypes and haplotypes, and similar PAI-1 levels, were seen in the proliferative retinopathy (PR) and non-proliferative retinopathy (NPR) patients, indicating that neither PAI-1 variants nor changes in PAI-1 levels were linked to DR severity. Multivariate analyses identified 4G/−844A and 4G/−844G haplotypes as negatively and positively associated, respectively, with DR, but not with DR severity (PR vs NPR) after adjusting for a number of covariates. Conclusion The present study identifies changes in PAI-1 levels and genetic variations at the PAI-1 locus as risk factors for DR, but not DR severity, that may serve as useful markers of increased DR susceptibility.