A search for cyclophilin-A gene variants in cyclosporine A-treated renal transplanted patients

Background: The cyclophilin A (CypA) - cyclosporine (CsA) complex promotes immune response. The variation at the CypA gene could explain CsA-pharmacokinetics and clinical outcomes among CsA-treated patients. Methods: The study included 290 kidney transplanted patients (65% male; mean age 51 ± 15 yr), treated with CsA. The five CypA- exons and the promoter region were analysed through single-strand conformation analysis, denaturing high performance liquid chromatography, and direct sequencing. The effect of a promoter polymorphism (−11 G/C) on gene expression was analysed in cell-cultures. Results: We found two polymorphisms in the promoter (−11 G/C) and exon 1 (+36 G/A). Genotype frequencies did not differ between patients according to their pharmacokinetics status. In vitro studies showed that −11 G/C affected gene expression. The −11 G allele was significantly associated with clinical nephrotoxicity (p = 0.006). The strongest predictors for nephrotoxicity were a donor age ≥55 yr, and the promoter GG + GC genotypes. Conclusions: Our work suggests that a CypA-promoter polymorphism (−11 G/C) could be associated with clinical nephrotoxicity. Replication of this study in other populations is necessary to define the role of CypA-variants in the main clinical outcomes among CsA-treated kidney-transplanted patients.