PI-027 - EFFECT OF GENETIC VARIANTS IN TSPYL ON THE PHARMACOKINETICS OF CYCLOSPORINE.

Q. Zhai¹, D. Moes¹, T. van Gelder¹, M. van der Lee¹, J. Homan van der Heide², J. Sanders³, F. Bemelman², J. de Fijter¹, J. Swen¹; ¹Leiden University Medical Center, Leiden, The Netherlands, ²Academic Medical Center, Amsterdam, The Netherlands, ³University Medical Center Groningen, Groningen, The Netherlands.

Background: Cyclosporine is widely used to prevent rejection following solid organ transplantation. Cyclosporine has a narrow therapeutic window and genetic variants in CYP3A have been linked to cyclosporine exposure. Transcriptional factors such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of several CYP enzymes, including CYP3A4 in vivo. We investigated whether genetic variants located in TSPYLs are associated with cyclosporine clearance.

Methods: Whole blood concentrations, clinical data and DNA for 295 kidney transcription patients who participated in the MECANO study (PMID: 27639190) were available. Five TSPYL single nucleotide polymorphisms (SNPs) rs3828743, rs10223646, rs6909133, rs1204807 and rs1204811 were genotyped with TaqMan assays. The influence of TSPYL variants on the cyclosporine clearance(l/h) was analyzed in a multivariate PK model accounting for body weight, steroids treatment and CYP3A4 genotype.

Results: After removing 10 patients with missing CYP3A4 genotype, 246 patients were successfully genotyped for TSPYL. In univariate analysis, only a TSPYL SNP rs3828743 was associated with a reduced cyclosporine clearance. Homozygous carriers of the variant allele showed a 14% lower clearance compared to wild-type and heterozygous carriers (Median: 15.24 vs. 17.63(l/h), p = 0.025). In the multivariate PK model, rs3828743 showed a consistent effect on cyclosporine clearance, with homozygous patients having a 16% lower clearance compared to the wild-type and heterozygous patients ( Median: 4.43 vs. 5.25 (I/h), p = 0.02).

Conclusion: The TSPYL polymorphism rs3828743 is significantly associated with the pharmacokinetics of cyclosporine and may partly explain decreased cyclosporine clearance.