Genetic Susceptibility to Diabetic Retinopathy in the Thrace Region: Role of IL-18 (−607 C/A, −137 G/C) and IL-8 (−251 A/T) Variations

Background/Objectives: Diabetic retinopathy (DR) is a leading cause of vision loss and is triggered by chronic inflammation and genetic predisposition. The aim of this study was to examine the connection between specific gene variations of interleukin IL-18 and IL-8 and the likelihood of developing DR, their part in the clinical severity of the condition, and their possible effect on kidney function in patients with diabetes. Methods: This study included 176 participants, 88 of whom were patients with DR and 88 of whom were healthy controls. Genotyping for IL-18 (−607 C/A, −137 G/C) was performed using allele-specific PCR, while IL-8 (−251 A/T) analysis was conducted via the PCR-restriction fragment length polymorphism (PCR-RFLP) method. A comprehensive documentation of demographic and clinical parameters was undertaken. Renal function was the subject of evaluation using the estimated glomerular filtration rate (eGFR). The statistical analyses included the independent samples t-test for continuous variables, the chi-squared test for categorical data, and binary logistic regression to assess genotype distributions. Adjusted multivariate logistic regression analysis was performed to account for potential confounding factors, and significance was determined using the Bonferroni correction (adjusted α = 0.005) for all genetic and clinical risk assessments. Results: A multivariate logistic regression analysis, adjusted for clinical variables, identified the IL-18 (−137) GC genotype (adjusted odds ratio (AOR) = 2.25, p = 0.002) and the IL-8 (−251) AT genotype (AOR = 1.98, p = 0.003) as significant independent risk factors for DR. Combined genotype analysis revealed that the IL-18/IL-8 (CA-AT) and (GC-AT) combinations were the most potent risk factors, with an adjusted odds ratio (AOR) of 3.10 (p = 0.002) for each. Additionally, specific IL-18 (CC-GC and CC-GG) haplotype combinations were identified as significant predictors of DR risk (AOR = 2.15, p = 0.004 and AOR = 0.38, p = 0.003, respectively). Exploratory subgroup analyses within the DR cohort revealed that certain genotypes, notably IL-18 (−607) CA, IL-18 (−137) GC, and IL-8 (−251) AT, remained significantly associated with the presence of vision-threatening diabetic retinopathy (VTDR) and ME following Bonferroni correction (p < 0.005). Finally, no statistically significant differences in eGFR levels were observed across the various genotype distributions (p > 0.05). Conclusions: Both IL-18 (−137 G/C) and IL-8 (−251 A/T) gene variations, and their synergistic combinations (e.g., CA-AT and GC-AT), significantly contribute to the risk and clinical severity of DR. Our adjusted multivariate analysis confirms that these variations are independent risk factors for DR, with high odds ratios observed in advanced clinical stages, such as VTDR and ME. Additionally, while hypertension, a family history of diabetes mellitus, and CAD were identified as significant clinical predictors, the lack of significant variance in eGFR across genotype distributions suggests that these genetic variations may influence DR pathology independently of gross renal impairment in our study population. In light of the observed associations, further investigation of these genetic markers in larger prospective cohorts is warranted to clarify the underlying inflammatory mechanisms and their broader clinical implications.