Association between Tacrolimus Variability and ABCB1/CYP3A5 Genetic Polymorphisms in Kidney Transplant Recipients

The aim of this study was to assess tacrolimus variability in kidney transplanted patients and its associations with genetic polymorphisms in CYP3A5(rs776746) and ABCB1(rs1045642) in North Macedonia. We conducted an observational study including 84 kidney transplant recipients who met inclusion criteria. Variability of tacrolimus was evaluated using the concentration-to-dose ratio (C0/D) and coefficient of variation (CV%). Single-nucleotide polymorphisms (SNPs) were identified using real-time polymerase chain reaction. Among the 84 patients, males predominated (70%), with a mean age of 37.57years. Analysis for variability revealed C0/D<1.05ng/ml/mg in 15% and CV>30% in 17% examined population. The majority of patients (86%) had the CYP3A5 GG genotype, whereas 14% carried at least one expresser allele (CYP3A5 AA/AG). Regarding ABCB1, 26% of patients had the CC genotype, 46% CT, and 27% TT. Patients carrying the CYP3A5 expresser genotype (AA/AG) demonstrated a significantly higher risk of low C0/D ratio (<1.05 ng/mL/mg) compared to non-expressers (58% vs. 8%; OR = 2.01; 95% CI: 1.114–3.624; p = 0.001). Additionally, expresser patients required significantly higher daily doses of tacrolimus to achieve target blood concentrations compared to non-expressers (5.11 ± 2.21 mg vs. 3.21 ± 1.78 mg, p = 0.014). No significant association was found between ABCB1 polymorphisms and tacrolimus variability parameters. This is first study in our country that explores and verifies the association between variability of tacrolimus and genetic polymorphisms in kidney transplant recipients. Our work advances the effort to tailor more personalized treatment, minimizing negative outcomes and adverse effects to the lowest achievable level.