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ABCB1 AND IMPDH FUNCTIONAL AND GENETIC CONTRIBUTIONS TO
TACROLIMUS AND MYCOPHENOLIC ACID THERAPY IN TRANSPLANT
PATIENTS
by
Jian Wang
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
August 2007
Copyright 2007 Jian Wang
Object Description
| Title | ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients |
| Author | Wang, Jian |
| Author email | jianw@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2007-05-11 |
| Date submitted | 2007 |
| Restricted until | Restricted until 30 July 2009. |
| Date published | 2009-07-30 |
| Advisor (committee chair) | Burckart, Gilbert J. |
| Advisor (committee member) |
Beringer, Paul Shen, Wei-chiang Richmond, Frances J. Watanabe, Richard M. |
| Abstract | 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. |
| Keyword | pharmacogenetics; ABCB1; IMPDH; transplantation; polymorphism |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m724 |
| Contributing entity | University of Southern California |
| Rights | Wang, Jian |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Wang-20070730 |
| Archival file | uscthesesreloadpub_Volume32/etd-Wang-20070730.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | ABCB1 AND IMPDH FUNCTIONAL AND GENETIC CONTRIBUTIONS TO TACROLIMUS AND MYCOPHENOLIC ACID THERAPY IN TRANSPLANT PATIENTS by Jian Wang A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) August 2007 Copyright 2007 Jian Wang |
