Abstract
BackgroundMounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes.MethodsData were retrieved in a systematic manner and analyzed using Review Manager and STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.ResultsNine studies with 1, 217 cases and 1, 459 controls were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests a marginal association of the 4G/5G polymorphism with diabetic retinopathy (for 4G versus 5G: OR 1.13, 95%CI 1.01 to 1.26; for 4G/4G versus 5G/5G: OR 1.30, 95%CI 1.04 to 1.64; for 4G/4G versus 5G/5G + 4G/5G: OR 1.26, 95%CI 1.05 to 1.52). In subgroup analysis by ethnicity, we found an association among the Caucasian population (for 4G versus 5G: OR 1.14, 95% CI 1.00 to 1.30; for 4G/4G versus 5G/5G: OR 1.33, 95%CI 1.02 to 1.74; for 4G/4G versus 5G/5G + 4G/5G: OR 1.41, 95%CI 1.13 to 1.77). When stratified by the average duration of diabetes, patients with diabetes histories longer than 10 years have an elevated susceptibility to diabetic retinopathy than those with shorter histories (for 4G/4G versus 5G/5G: OR 1.47, 95%CI 1.08 to 2.00). We also detected a higher risk in hospital-based studies (for 4G/4G versus 5G/5G+4G/5G: OR 1.27, 95%CI 1.02 to 1.57).ConclusionsThe present meta-analysis suggested that 4G/5G polymorphism in the PAI-1 gene potentially increased the risk of diabetic retinopathy in type 2 diabetes and showed a discrepancy in different ethnicities. A higher susceptibility in patients with longer duration of diabetes (more than 10 years) indicated a gene-environment interaction in determining the risk of diabetic retinopathy.
Highlights
Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy
Search strategy In this meta-analysis, a comprehensive literature research of the US National Library of Medicine’s PubMed database was conducted using research terms including ‘plasminogen activator inhibitor-1’, ‘PAI1’, ‘4G/5G’, ‘polymorphism’, ‘type 2 diabetes’, ‘diabetic retinopathy’ and the combined phrases to obtain all genetic studies on the relationship between PAI-1 4G/5G polymorphism and Diabetic retinopathy (DR) risk
Four studies in which the average diabetes duration in all the subgroups was longer than 10 years were enrolled together and compared with the other five studies in which the diabetes duration was shorter than 10 years
Summary
Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes. PAI-1 activity, which is affected by PAI-1 gene polymorphisms and metabolic determinants, is elevated in DR [13]. Compared with other PAI-1 variants, the most significant variation in PAI1 expression resides in a common single-base-pair guanine insertion/deletion polymorphism (4G/5G) within the promoter region of the PAI-1 gene at nucleotide position -675 [11,14]. Unlike the 5G allele that binds a transcription repressor protein, resulting in low PAI-1 expression, the 4G allele does not bind a transcription repressor, conferring a ‘high PAI-1 expressor’ nature to the allele [15]
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