Unraveling the genes that contribute to the pathogenic risk of DR has been one of the major foci of basic research in DR over the past few decades. A large number of putative genes and genetic variants have been reported to be associated with higher risk of DR. A genome-wide association study performed on Mexican-Americans found several SNPs and genes associated with severe DR. None of these loci have been previously linked to DR or diabetes itself . Another genome-wide association study on Taiwanese populations identified five loci not previously associated with DR susceptibility in T2D . This suggests that, until now, no genes have achieved widespread acceptance as conferring high risk of DR in patients with T2D . After a review of the meta-analyses of DR-related gene polymorphisms, only the C677T polymorphism in the methylenetetrahydrofolate reductase gene was detected to moderately augment the risk of DR in T2D overall [34, 35]. The Gly82Ser polymorphism in the receptor for advanced glycation end products gene might be considered a risk factor for DR in Asian populations. Moderate evidence was founded for a correlation between the angiotensin-converting enzyme gene and proliferative DR . However, neither the angiotensin-converting enzyme gene insertion/deletion [36–38] nor the vascular endothelial growth factor -634C/G gene  showed a significant relationship with DR, either overall or in ethnicity subgroups in meta-analysis so far.
The results of this meta-analysis suggest that PAI-1 4G/4G polymorphism was overall marginally significantly associated with DR risk in T2D. In the stratified analysis, significant associations were observed with Caucasian ethnicity, diabetes duration longer than 10 years and hospital-based studies. To the best of our knowledge, this is the first meta-analysis assessing the association between PAI-1 gene polymorphism and DR.
The earliest investigation into PAI-1 polymorphism and DR risk, reported by Nagi et al., revealed a positive relationship between the 4G allele of PAI-1  and DR risk in Pima Indians, whose incidence of diabetes, particularly non-insulin-dependent diabetes, was extremely high [40, 41]. However, in the subsequent studies in Caucasian populations, a trend of studies with a lack of association was suggested [16, 18, 20, 21]. But in a recent larger case-control study in Tunisia that contained a total of 856 adult patients with T2D, Ezzidi et al. reported a significantly higher frequency of the 4G/4G genotype (OR 1.64, 95%CI 1.10 to 2.43), indicating 4G/4G in PAI-1 locus as a risk factor for DR . All the studies in East Asian populations showed no relationship between 4G/5G polymorphism and DR risk [22–24]. Our meta-analysis confirmed that the 4G/4G genotype of the PAI-1 carried more risk in Caucasian but not Asian participants, even though the overall effect was positive. The differences in ethnic backgrounds, lifestyle, nutrition and living environment may partly explain this discrepancy . We also found a marginally significant susceptibility to DR of T2D between PAI-1 4G/5G polymorphism to the population with longer duration of T2D. This subgroup analysis manifested a gene-environment interaction and highlighted the need for implementing rigorous case-selective criterion in future studies.
We also observed inconsistent results between hospital-based studies and population-based studies, which may be explained by the biases in hospital-based studies. Control cases in hospital-based studies may be less representative of the general population than those from population-based studies. Genes do not work in isolation; instead, complex molecular networks and cellular pathways are often involved in disease susceptibility . Taking into account that DR is a complex disease with multifactorial, polygenic and environmental influences, a minor contributing pathogenic role of the PAI-1 polymorphism in specific cases in DR and in co-operation with other factors cannot be totally excluded.
Several potential limitations existed in our meta-analysis and our results should be interpreted with caution. First, as no correction for multiple testing was performed in this meta-analysis, false positive results may have been induced in some fraction because of the application of multiple statistical tests, which would increase the probability of type I errors. Second, our meta-analysis is based on unadjusted estimates because of a lack of original data. For example, the accurate disease time-course of individual patients was unavailable, which may potentially have affected the results where our classification criterion was according to the mean value of the diabetes duration. Third, this meta-analysis was limited by the small sample size - especially in subgroup analysis - though the Egger's test gave no publication bias . Fourth, the existing studies lacked information about potential gene-gene interactions. Last, genotyping methods were different among selected studies, which might affect results. This discrepancy indicates the need to implement rigorous quality control procedures in future studies.