#71-OR
MDR1 EXON26 GENOTYPE PREDICTS TREATMENT-RESISTANT REJECTION IN LUNG TRANSPLANT PATIENTS AS ASSESSED BY LOGISTIC REGRESSION ANALYSIS.
HongXia Zheng M.D. , Adriana Zeevi Ph.D. , Kenneth McCurry M.D. , Erin Schuetz Ph.D. , Steven Webber M.D. , Julianne Ristich M.S. , Jiong Zhang Ph.D. , Aldo Iacono M.D. , James Dauber M.D. , Kevin McDade B.S. , Diana Zaldonis R.N. , Jatinder Lamba Ph.D. and Gilbert Burckart Pharm.D. . Los Angeles CA, University of Southern California, 90033, Department of Pharmacy ; Pittsburgh PA, University of Pittsburgh, 15213, Departments of Pathology, Surgery and Medicine and Memphis TN, St. Jude Children
s Research Hospital, 38105, Department of Pharmacology .
P-glycoprotein (P-gp) is a membrane transporter and is encoded by the gene MDR1. Since many immunosuppressive agents are P-gp substrates, MDR1 genotypes may have an association with graft rejection. The objective of this study was to evaluate the risk factors, including MDR1 and cytokine polymorphisms, associated with acute persistent rejection (APR) in lung transplant (LTx) patients. METHODS: 132 adult LTx patients were studied. MDR1 exon26 and 21, CYP3A5, and cytokine genotyping for 5 cytokines were performed. Logistic regression analysis was used to identify the predictors using SPSS. The dependent variable was the presence or absence of APR based on lung biopsies during the first postoperative year. The independent variables were MDR1 exon26 and exon21, CYP4503A5 and cytokine polymorphisms, survival status and HLA mismatches. RESULTS: Only MDR1 exon26 was independently associated with APR (p=0.003; Odds Ratio=3, 95% CI 1.0-11.2). For MDR1 exon26, 67% of patients in the CC wild-type group had APR, in comparison to 75% for CT and 42% for TT patients (p=0.03). DISCUSSION: This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The MDR1 exon26 C allele is associated with increased P-gp function, which could lead to altered disposition of immunosuppressive agents or altered T-cell resistance. We conclude that the MDR1 exon26 genotype is associated with APR in LTx patients, and that the homozygous mutant genotype has the lowest incidence of APR.