ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patient

Tacrolimus and mycophenolic acid (MPA) are commonly used in clinic to prevent rejection in transplant recipients. The influence of ABCB1 polymorphisms on tacrolimus dosing has been questioned in previous studies with contradictory findings. Inosine 5'-monophosphate dehydrogenase (IMPDH), catalyzes the rate-limiting step of de novo pathway for purine synthesis, and is the major target of the immunosuppressive drug MPA. Variants in genes IMPDH may account for the interindividual variability in baseline enzyme activity, immunosuppressive efficacy and side effects in transplant recipients receiving MPA. In this study, three ABCB1 haplotypes CGC, TTT and CGT accounted for 44.1%, 40.7% and 7.6% of the total haplotypes, respectively in a total of 91 lung transplant patients. The tacrolimus [L/D] value in the CGC-CGC haplotype was significantly lower than in patients with CGC-TTT and TTT-TTT genotypes throughout the first post transplant year. As for IMPDH2, nine genetic variants were identified with frequencies of the rarer alleles ranging from 0.5--10.2%. A novel nonsynonymous variant L263F was identified, and the kinetic assay demonstrated that the IMPDH activity of L263F variant was decreased to 10% of the wild type. Seventeen genetic variants were identified in the IMPDH1 gene in our study, with frequencies of the rarer alleles ranging from 0.2--42.7%. Six tagging SNPs were selected to present two haplotype blocks in IMPDH1. No differences in the allele frequencies between ethnic groups were observed except SNP rs2288553. No significant associations were observed between each IMPDH1 SNP and incidence of leukopenia in MPA treated transplant patients. Two SNPs, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute rejection in the first year post transplantation. Both of these SNPs had positive and negative predictive values for acute rejection greater than 50%. This study demonstrates that (1) analysis using the haplotypes derived from three common ABCB1 polymorphisms is predictive for tacrolimus dosing in lung transplant patients when eliminating the confounder CYP3A5 genotype; (2) IMPDH1 polymorphisms are associated with the incidence of biopsy-proven acute rejection in the first year post transplantation. Future studies of the multi-factorial nature of acute rejection should take into account IMPDH1 polymorphisms in MPA treated patients.