Associations between polymorphisms in target, metabolism, or transport proteins of mycophenolate sodium and therapeutic or adverse effects in kidney transplant patients.

OBJECTIVES Different associations between single nucleotide polymorphisms (SNPs) in cellular target, metabolism enzymes or transport proteins, and biopsy-proven acute rejection (BPAR) or adverse events have been reported in transplant patients receiving mycophenolate mofetil. This work aimed to study these in patients on enteric-coated mycophenolate sodium (EC-MPS). PATIENTS AND METHODS The study included 189 renal transplant patients from the DOMINOS trial. Fifteen SNPs in IMPDH2, IMPDH1, ABCC2, SLCO1B3, UGT1A8, UGT1A9, UGT2B7, CYP2C8, HUS1, and IL12A were genotyped in all patients. Associations between SNPs and the first event of BPAR or diarrhea were investigated using multivariate logistic regressions. Associations between SNPs and leukopenia or anemia at nine different visits between days 0 and 190 after transplantation were studied using time-dependent Cox proportional hazards regression models. RESULTS Multivariate analyses showed that the CYP2C8 rs11572076 wild-type genotype was associated significantly with a lower risk of leukopenia [GG vs. GA: hazard ratio (95% confidence interval) 0.14 (0.03, 0.59), P=0.00783]. Higher EC-MPS doses and the UGT2B7 c.-840 G>A variant allele were associated with an increased risk of anemia [EC-MPS per unit dose increase: 1.004 (1.003, 1.005), P<0.0001; UGT2B7 GA vs. AA: 1.65 (1.12, 2.43), P=0.01043; GG vs. AA: 1.88 (1.23, 2.88), P=0.00343]. However, no significant association was found between any of the SNPs studied and diarrhea or BPAR. CONCLUSION Two pharmacogenetic associations reported previously with mycophenolate mofetil were found in a population of 189 renal transplant patients treated with EC-MPS.