Identifying the genetic risk factors of diabetic retinopathy (DR) is essential for discovering the potential pathogenesis of DR. This study determined the association of DR with five single nucleotide polymorphisms (SNPs) specifically in type 2 diabetes mellitus (T2DM) patients, including rs10061133(MIR-449B), rs17883901(GCLC), rs2070744(eNOS), rs3759890 (SORD) and rs7754561 (ENPP1). A total of 1433 individuals were enrolled in this study, comprising healthy controls (ctrls = 480), individuals with diabetes mellitus without retinopathy (DNR = 480), non-proliferative DR(NPDR = 378), and proliferative DR(PDR = 95). The five SNPs were genotyped utilizing Mass ARRAY MALDI-TOF technology. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for the risk of genotype and allele. We performed a literature search in PubMed published before July 16, 2023. The Newcastle Ottawa Scale was used to evaluate the overall quality of the case-control studies. Consequently, we found that there were statistically significant differences between PDR cases and healthy controls for rs10061133 (P = 0.007, OR = 1.59, 95% CI = 1.32-2.23) and rs17883901 (P = 0.020, OR = 1.67, 95% CI = 1.08-2.57), rs17883901 was significantly associated with NPDR (P = 0.023, OR = 1.39, 95% CI = 1.05-1.85), there was a significant association between DR cases and healthy controls (P = 0.048, OR = 1.22, 95% CI = 1.00-1.48) for rs3759890 in the allelic model. DR show no relationships with the other two SNPs compared to healthy controls. In multivariate analyses comparing the DR and DNR groups, rs7754561(A), rs10061133(G), and rs17883901(A) were identified as risk loci for DR in individuals with a duration of diabetes of ≥5 years (P = 0.0023, P = 0.0037, and P = 0.0376, respectively). Furthermore, individuals carrying rs10061133(G) exhibited a higher risk of DR in the hyperglycemic group (glucose ≥8 mmol/L). Secondly, we showed that one polymorphism in eNOS (rs2070744, T >
C) showed a suggestive association with DR in the meta-analysis (allelic model:P <
0.05, OR = 1.18, 95% CI: 1.07-1.30, Z = 3.46, I