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Identification of novel and interacting pharmacogenetic variants that determine differential sirolimus clearance in children with neurofibromatosis type 1 and plexiform neurofibromas

Wright, Jordan M, M.D.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377872510

Abstract Details

2013, MS, University of Cincinnati, Medicine: Clinical and Translational Research.
Purpose: Sirolimus is an immunosuppressive medication that acts through inhibition of the Mammalian Target of Rapamycin (MToR) pathway. It is widely used in organ transplantation and more recently in treatment of malignancy. CYP3A5*3 polymorphisms have been shown to influence sirolimus clearance in solid organ transplant patients, but effects of other drug metabolism enzyme and transporter (DMET) gene polymorphisms have not been investigated. In addition, other populations in which sirolimus is used have not been investigated for polymorphisms associated with metabolism. We hypothesized that additional variants, alone or in combination, would better predict sirolimus clearance in patients with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN). Methods: A phase II study had pharmacokinetic parameters measured in 42 children with NF1 who were receiving sirolimus. Patients were also genotyped for 1,931 known polymorphisms using the DMET Microarray (Affymetrix). Statistical analyses initially calculated correlation coefficients for all 1,931 polymorphisms to allometric clearance (CL/[(Wtx70)0.75]). Missing values in the dataset were imputed, and then multiple regression analysis for a subset of the most highly correlated polymorphisms was performed. Results: The final multiple regression analysis included eight interaction terms and three linear terms. The three linear DMET genes that significantly and independently influenced sirolimus clearance were the multidrug resistance-associated protein ABCC5 (p=<0.0001), nucleoside transporter SLC28A2 (p=0.0012), and UDP-Glucuronosyltransferase protein UGT2B7 (p=<0.0001). SLC28A2 and UGT2B7 had the strongest effect size, with the log of allometric clearance increasing by 0.303 and decreasing by 0.233, respectively, with each polymorphic allele copy. The 8 interaction terms in the regression model included SLC28A2 interacting with the aldehyde dehydrogenase ALDH3A1 (p=0.0003), organic cation transporter SLC22A1 (p =0.0005), and glutathione-S-transferase GSTM3 (p=0.0002). SLC22A1 interacted with ALDH3A1 (p=0.0002), UDP-Glucuronosyltransferase UGT2B7 (p=0.001), and the copper transporter ATP7A (p=0.0008). GSTM3 interacted with ATP7A (p=0.038) and ALDH3A1 (p=0.0003). The model had an overall F-value of 13.29, p-value of <0.0001, and R-square of 0.83. Conclusion: Our novel genotype based regression model was able to significantly improve the prediction of patient dosing since the regression model can estimate 83% of variability in allometric drug clearance for our patient population based on genotype alone. Future studies in larger populations are needed to confirm this model and possibly improve sirolimus' safe and effective use. This work also establishes a novel approach that could be used for identifying pharmacogenetic guided dosing of other drugs and chemotherapy.
Paul Succop, Ph.D. (Committee Chair)
John Perentesis, M.D. (Committee Member)
22 p.
Surgery
Sirolimus; Pharmacogenetics; Pharmacogenomics; Neurofibromatosis; Plexiform Neurofibroma

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Citations

  • Wright, M.D., J. M. (2013). Identification of novel and interacting pharmacogenetic variants that determine differential sirolimus clearance in children with neurofibromatosis type 1 and plexiform neurofibromas [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377872510

    APA Style (7th edition)

  • Wright, M.D., Jordan. Identification of novel and interacting pharmacogenetic variants that determine differential sirolimus clearance in children with neurofibromatosis type 1 and plexiform neurofibromas. 2013. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377872510.

    MLA Style (8th edition)

  • Wright, M.D., Jordan. "Identification of novel and interacting pharmacogenetic variants that determine differential sirolimus clearance in children with neurofibromatosis type 1 and plexiform neurofibromas." Master's thesis, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377872510

    Chicago Manual of Style (17th edition)

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© 2013, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.