Associations of IL-2, IL-6 and IL-10 Gene Polymorphisms with Biochemical Parameters and Calcineurin Inhibitor Dosing in Kidney Transplant Recipients

Background/Objectives: Kidney graft dysfunction remains a major challenge limiting long-term transplant survival despite advances in immunosuppressive therapy. Cytokine signaling pathways have been implicated in the regulation of alloimmune responses and chronic inflammation, but their contribution to long-term graft function and immunosuppressant pharmacokinetics remains incompletely understood. This study investigated associations among selected cytokine gene polymorphisms (IL-2 −330T>G, IL-6 −174G>C, and IL-10 −1082A>G), biochemical and hematological parameters, and calcineurin inhibitor (tacrolimus and cyclosporine) dosing in kidney transplant recipients. Methods: A total of 394 kidney transplant recipients receiving tacrolimus or cyclosporine were enrolled. Genotyping of IL-2 rs2069762, IL-6 rs1800795 and IL-10 rs1800896 was performed using real-time PCR. Clinical, biochemical, and pharmacokinetic data were analyzed using univariate and multivariate statistical models adjusted for relevant demographic and clinical covariates. Results: IL-2 rs2069762 and IL-6 rs1800795 polymorphisms were not associated with clinically relevant differences in biochemical parameters, calcineurin inhibitor dosing, or transplant outcomes. For IL-10 rs1800896, no statistically significant associations were observed with cyclosporine A blood levels, dose, or C/D ratio. Among tacrolimus-treated patients, the regression model for the C/D ratio was borderline significant (F(2,207) = 3.048, p = 0.050, R2 = 0.029). However, the genotype-specific association for the heterozygous GA genotype versus AA was not statistically significant in the unadjusted model (B = −0.462, 95% CI: −0.97 to 0.04, p = 0.072) or after adjustment for age, sex, and time since transplantation (B = −0.450, 95% CI: −0.95 to 0.05, p = 0.078). Although univariate analyses identified associations between IL-10 rs1800896 and selected biochemical parameters, these findings were not confirmed in multivariable models. No significant associations were observed between the analyzed cytokine polymorphisms and graft rejection, graft survival, patient survival, or clinically relevant markers of kidney graft function. Conclusions: The results suggest a possible, although not statistically significant, association between IL-10 rs1800896 and tacrolimus exposure, as assessed by the C/D ratio. This observation should be considered preliminary and interpreted with caution. The lack of CYP3A5 genotyping and functional assessment of IL-10 activity, inflammation, and CYP3A-dependent metabolism further limits the interpretation of this potential association. Larger prospective studies with comprehensive pharmacogenetic and functional characterization are needed to determine whether IL-10 rs1800896 contributes to interindividual variability in tacrolimus exposure and whether it may have potential applications in individualized immunosuppressive therapy.