Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T > C polymorphism.
OBJECTIVE
The active metabolite of mycophenolate mofetil (MMF), mycophenolic acid, inhibits the activity of the target enzyme inosine monophosphate dehydrogenase (IMPDH). The aim of this study was to correlate eight different single nucleotide polymorphisms of the IMPDH type II gene to the activity of the IMPDH enzyme to explain between-patient differences in IMPDH activity.


RESULTS
In a prospective study, we measured IMPDH activity, mycophenolic acid plasma concentrations, and eight polymorphisms of IMPDH type II in de novo kidney transplant recipients, 6 days posttransplantation while on MMF treatment. Polymorphisms in the IMPDH type II gene were only observed for the IMPDH type II 3757T > C (rs11706052) single nucleotide polymorphism. Ten of 101 patients (10%) were heterozygous and two of 101 patients (2%) homozygous for IMPDH type II 3757T > C. The allele frequency was 6.9%. The IMPDH activity over 12 h (AUC(act)) was 49% higher for patients with an IMPDH type II 3757C variant [n = 12 vs. n = 68; 336 (95% confidence interval: 216-521) vs. 227 (95% confidence interval: 198-260) hmicromol/s/mol adenosine monophosphate; P = 0.04]. The IMPDH activity measured before transplantation (Act(pre-Tx)) was not significantly different between IMPDH type II 3757TT wild-type and variant carrier patients (P = 0.99).


CONCLUSIONS
We report that the IMPDH type II 3757T > C polymorphism is associated with an increased IMPDH activity in MMF-treated renal transplant patients. This polymorphism explains 8.0% of the interpatient variability in IMPDH activity.
Sombogaard
Ferdi
F
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
van Schaik
Ron H N
RH
Mathot
Ron A
RA
Budde
Klemens
K
van der Werf
Marloes
M
Vulto
Arnold G
AG
Weimar
Willem
W
Glander
Petra
P
Essioux
Laurent
L
van Gelder
Teun
T
D000328:Adult; D019540:Area Under Curve; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000235:genetics*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid