Genetic polymorphisms influence mycophenolate mofetil-related adverse events in pediatric heart transplant patients.
BACKGROUND
Mycophenolate mofetil (MMF) is an effective and commonly used immunosuppressant but has frequent adverse events. Genetic polymorphisms may contribute to variability in MMF efficacy and related complications. In this study we explore the distribution frequencies of common single nucleotide polymorphisms (SNPs) of IMPDH1, IMPDH2 and ABCC2 and investigate whether these SNPs influence MMF adverse events in 59 pediatric heart recipients.


METHODS
Genotypes were assessed by TaqMan analysis of: ABCC2 rs717620; IMPDH2 rs11706052; and IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294 and rs2228075. Gastrointestinal (GI) intolerance was defined as diarrhea, vomiting, nausea or abdominal pain requiring dose-holding for >48 hours or MMF discontinuation. Bone marrow toxicity was evaluated using Common Terminology Criteria for Adverse Events Version 3 (CTCAE).


RESULTS
GI intolerance occurred in 21 patients, and 21 had bone marrow toxicity. The ABCC2 rs717620 A variant was significantly associated with GI intolerance leading to drug discontinuation (p < 0.001); the IMPDH1 rs2278294 A variant and rs2228075 A variant were also associated with greater GI intolerance (p = 0.029 and p = 0.002, respectively). The IMPDH2 rs11706052 G variant was associated with more frequent neutropenia requiring dose-holding (p = 0.046).


CONCLUSIONS
In this small sample of pediatric heart transplant patients receiving MMF, ABCC2, IMPDH1 and IMPDH2 SNPs were associated with MMF GI intolerance and bone marrow toxicity. Thus, genetic polymorphisms may directly influence MMF adverse events.
Ohmann
Erin L
EL
Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania 15201, USA.
Burckart
Gilbert J
GJ
Brooks
Maria M
MM
Chen
Yan
Y
Pravica
Vera
V
Girnita
Diana M
DM
Zeevi
Adriana
A
Webber
Steven A
SA
D000293:Adolescent; D000483:Alleles; D001854:Bone Marrow Cells / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005759:Gastroenteritis / Q000139:chemically induced* / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007223:Infant; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D007168:IMP Dehydrogenase; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; C000715087:ABCC2 protein, human; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human