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 > or =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.
Moscoso-Solorzano
Grace Tamara
GT
Servicio de Nefrología-Hospital Central de Asturias, Oviedo, Spain.
Ortega
Francisco
F
Rodríguez
Isabel
I
García-Castro
Mónica
M
Gómez
Ernesto
E
Díaz-Corte
Carmen
C
Baltar
José M
JM
Alvarez
Victoria
V
Ortiz
Alberto
A
Coto
Eliecer
E
D000328:Adult; D002851:Chromatography, High Pressure Liquid; D021984:Cyclophilin A / Q000235:genetics*; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D021984:Cyclophilin A