The effect of polymorphism on sirolimus in renal transplant recipients: a meta-analysis.

Background: Sirolimus (SRL) is an immunosuppressive drug and substrate of the P-glycoprotein (P-GP) encoded by . The relationship between polymorphism and the pharmacokinetics of SRL in different studies were conflicting in renal transplant recipients. Thus, this meta-analysis aims to investigate the influence of C3435T, C1236T, and G2677T/A polymorphisms on the dose-adjusted trough level (C/D) of SRL in renal transplant recipients.

Methods: PubMed, Embase, and the Cochrane Library were searched for relevant studies. The quality of each eligible study was assessed according to Newcastle-Ottawa Scale. The STATA 15.0 was adopted to perform the meta-analysis. The fixed-effects model was used for pooled results with low heterogeneity (I ≤50%); otherwise, the random-effects model was used.

Results: A total of 6 studies were included in the meta-analysis. Results of pooled analysis showed no significant association of SRL C/D ratio with C3435T polymorphism. The subgroup analysis based on different ethnic groups and different time-points after SRL initiation in renal transplant recipients were also conducted. No significant association was observed in these subgroups. Significant associations were showed between C1236T polymorphism and the C/D ratio of SRL in the homozygous model (TT CC; WMD: -45.54; 95% CI: -75.15, -15.94; P=0.003), and also in subgroup of Caucasian (TT CC; WMD: -46.57; 95% CI: -91.90, -1.25; P=0.044 and TT CC + CT; WMD: -52.10; 95% CI: -95.38, -8.82; P=0.018). Significant differences were found in association between the G2677T/A polymorphism and the C/D ratio of SRL, including the homozygous model (TT GG; WMD: -76.47; 95% CI: -126.37, -26.58; P= 0.003), the heterozygous model (GT GG,WMD: 178.62; 95% CI: 125.03, 232.22; P= 0.000), the dominant model (GT + TT GG; WMD: 82.23; 95% CI: 36.28, 128.17; P=0.000), the recessive model (TT GG + GT; WMD: -179.38; 95% CI: -283.33, -75.42; P=0.001), and the over-dominant model (GT GG + TT; WMD: 199.44; 95% CI: 84.84, 314.05; P=0.001).

Conclusions: No significant association exists between C3435T polymorphism and the C/D ratio of SRL in renal transplant recipients. To achieve target therapeutic concentrations, C1236T homozygous mutant TT genotype will require a higher dose of sirolimus than wild type GG, especially in Caucasian renal transplant recipients. G2677T/A TT genotype will also need a higher dose of sirolimus genotype. Genotyping of might help to improve the individualization of SRL for renal transplant recipients. Further studies are expected to provide high-quality evidence.