title: Genetic polymorphisms of UGT1A8, UGT1A9 and HNF-1α and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid.
abstract: Mycophenolic acid (MPA), a widely used immunosuppressant, has a complex metabolism that involves a number of enzymes. Some of its metabolites are thought to be the cause of gastrointestinal (GI) side effects. In this study, we investigated whether polymorphisms of UDP-glucuronosyltransferases (UGT1) A8, 1A9, and hepatocyte nuclear factor (HNF1α) genes or pharmacokinetic parameters of mycophenolic acid (MPA) were associated with the severity of GI symptoms in patients receiving MPA therapy. A total of 109 kidney transplant patients taking mycophenolic acid (MPA) derivatives were genotyped for UGT1A8, 1A9 and HNF1α genes. Among these, a total of 15 patients were participants in the pharmacokinetic study. Severity of GI symptoms was assessed using a validated Gastrointestinal Symptom Rating Scale (GSRS). The overall and subscale GSRS scores were measured at 1 week (baseline), 2 weeks, 3 months and 6 months post-transplantation. In the case of the pharmacokinetic study, EC-MPS was administered and a total of nine blood samples were obtained at -1, 0, 0.5, 1, 2, 4, 6, 8, and 12h. Genotypes of UGT1A8 were significantly associated with the overall GSRS scores at week 1 (p=0.02) and week 2 (p=0.036). Subscales were only statistically significant for constipation at week 1 (p=0.002) and indigestion at week 2 (p=0.02), while UGT1A9 was only significant for the constipation at week 1 (p=0.04). HNF1α genotypes were significantly different at week 1 in the overall GSRS (p=0.004), and for abdominal pain (p=0.04), acid reflux (p=0.036) and constipation subscales (p=0.04). In addition, abdominal pain was statistically significantly different at 3 months and 6 months after transplantation (p=0.03 and 0.02, respectively). In the case of the pharmacokinetic study, we have found some correlations between MPAC0 and constipation (p=0.02) where MPAAUC was correlated with acid reflux (p=0.02) and constipation (p=0.012), MPAGCL/F was correlated to acid reflux, indigestion, constipation and the sum of the GSRS scores (p=0.037, p=0.032, p=0.033 and p=0.04, respectively). Multinomial regression analysis for MPAGCL/F showed a statistical significance for the subscale indigestion and the sum of the GSRS (p=0.033 and p=0.037, respectively). Our data suggests that among patients receiving MPA the UGT1A9 alleles might play a role in determining the severity of early GI side effects, while the HNF1α allele appears to be associated with a later effect as well as early side effects. Our data also showed that some kinetic parameters might predict MPA side effects.
authors.affiliation: Mendez National Institute of Transplantation, Los Angeles, CA, United States; Saint Vincent Medical Center, Los Angeles, CA, United States; Western University of Health Sciences, Pomona, CA, United States.
authors.forename: Don
authors.initials: D
authors.lastname: Vu
authors.forename: Eglis
authors.initials: E
authors.lastname: Tellez-Corrales
authors.forename: Jaewook
authors.initials: J
authors.lastname: Yang
authors.forename: Yasir
authors.initials: Y
authors.lastname: Qazi
authors.forename: Tariq
authors.initials: T
authors.lastname: Shah
authors.forename: Robert
authors.initials: R
authors.lastname: Naraghi
authors.forename: Ian V
authors.initials: IV
authors.lastname: Hutchinson
authors.forename: David I
authors.initials: DI
authors.lastname: Min
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D000903:Antibiotics, Antineoplastic; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C000715591:UGT1A9 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C454320:UDP-glucuronosyltransferase, UGT1A8; D009173:Mycophenolic Acid
keywords: GSRS; Gastrointestinal Symptom Rating Scale; Gastrointestinal side effect; Genetic polymorphism; HNF1α; MPA; Mycophenolic acid; SNP; UDP-glucuronosyltransferases; UGT1A8; UGT1A9; UGTs; mycophenolic acid; single nucleotide polymorphism