Background: The large interindividual variability in the genetic polymorphisms of sirolimus (SIR)- metabolizing enzymes, transporters, and receptors can lead to qualitatively and quantitatively distinct therapeutic responses.
Objective: We examined the impact of numerous candidate single-nucleotide polymorphisms (SNPs) involved in the trough concentration of SIR-based immunosuppressant regimen.
Methods: This is a retrospective, long-term cohort study involving 69 renal allograft recipients. Total DNA was isolated from recipient blood samples and trough SIR concentrations were measured by microparticle enzyme immunoassay. Genome sequence reading was targeted based on next-generation sequencing. The association of tagger SNPs to SIR trough concentrations with non-genetic covariate adjusting was analyzed using logistic regression.
Results: A total of 300 SNPs were genotyped in the recipient DNA samples using target sequencing analysis. Only the SNP of CYP3A4 (Ch7: 99361466 C>T, rs2242480) had a significantly higher association with SIR trough concentration as compared to the other 36 tagger SNPs. The mean trough SIR concentration of patients in the CYP3A4 rs2242480-CC group was more significant compared to that of the CYP3A4 rs2242480-TC and TT group, respectively 533.3; 157.4 and 142.5 (ng/ml)/mg/kg, P<0.0001. After adjusting the SNPs, there was no significant association between clinical factors such as age, follow-up period, the incidence of delayed graft function, immunosuppression protocol, and sex with SIR trough concentration.
Conclusion: These findings indicated a significant association of polymorphism in the CYP3A4 (Ch7: 99361466 C>T, rs2242480) with SIR trough concentration after 1-year administration in patients who have undergone kidney transplantation.
Keywords: Renal transplantation; SNPs; pharmacogenetics; sirolimus; targetted sequencing; trough concentration.
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