title: Genetic polymorphisms of MRP2 and UGT2B7 and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid.
abstract: The aim of this study was to determine the relationship between single nucleotide polymorphisms in multidrug resistance protein 2 (MRP2) and uridine diphosphate glucuronosyltransferase (UGT) 2B7 and the severity of gastrointestinal (GI) symptoms in patients receiving mycophenolic acid (MPA). A total of 67 renal transplant recipients taking MPA derivatives were included in the study. Genotypes for MRP2 C-24 T and UGT2B7 C802 T were determined. The incidence and severity of GI symptoms were assessed using the validated Gastrointestinal Symptom Rating Scale (GSRS) at baseline, 2 weeks, 3 months, and 6 months after transplantation. The mean overall GSRS score and the score on the subscale for diarrhea were compared using the Kruskal-Wallis test. The overall GSRS scores (23.5 +/- 4.5 vs. 26.7 +/- 9.9, P = 0.68) or diarrhea subscores (3.5 +/- 0.9 vs. 5.1 +/- 3.3, P = 0.08) were not significantly different among patients with the heterozygous variant MRP2 C-24 T and those with the homozygous wild type. For UGT2B7, the overall mean GSRS scores were significantly different between the homozygous wild type and the variant type (CC vs. CT + TT, 29.2 +/- 9.3 vs. 24.0 +/- 8.2, P = 0.009), although diarrhea subscale scores did not reach statistical significance (CC vs. CT + TT, 5.7 +/- 4.1 vs. 4.1 +/- 1.9, P = 0.13). When the genotypes for MRP2 and UGT2B7 were considered together, patients with the variant forms of MRP2 and UGT2B7 had significantly lower overall GSRS scores (CC-CC vs. CT-CT/TT, 22.5 +/- 4.3 vs. 30.1 +/- 10.1, P = 0.04) and diarrhea subscale scores compared to wild type (CC-CC vs. CT-CT/TT, 3.4 +/- 0.7 vs. 6.2 +/- 4.4, P = 0.03). However, there were no differences in GSRS scores between patients receiving either mycophenolic mofetil (MMF) or enteric-coated mycophenolic acid (EC-MPA) regardless of whether the patients were receiving different calcineurin inhibitors. In conclusion, this study suggests that among patients receiving MPA, those with UGT2B7 variant genotypes are protected from the GI side effects of MPA regardless of the formulation used or concurrent calcineurin inhibitors administered. MRP2 genotypes did not show significant differences in GI side effects among patients taking MPA therapy.
authors.affiliation: Mendez National Institute of Transplantation, Los Angeles, California, USA.
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Yang
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Lee
authors.forename: Ian V
authors.initials: IV
authors.lastname: Hutchinson
authors.forename: Vera
authors.initials: V
authors.lastname: Pravica
authors.forename: Tariq
authors.initials: T
authors.lastname: Shah
authors.forename: David I
authors.initials: DI
authors.lastname: Min
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D019703:Calcineurin / Q000134:cerebrospinal fluid; D014453:Glucuronosyltransferase / Q000235:genetics*; D006084:Graft Rejection; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016030:Kidney Transplantation; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011795:Surveys and Questionnaires; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D019703:Calcineurin; D014453:Glucuronosyltransferase; D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4