This proposal represents a request for continued funding of the Mayo Clinic Pharmacogenomics Research Network (PGRN) grant "Pharmacogenetics of Phase II Drug Metabolizing Enzymes". The Mayo PGRN is an integrated, multidisciplinary, pharmacogenomic research effort based on a decades-long focus at Mayo on the pharmacogenetics of phase II (conjugating) drug metabolizing enzymes. The Mayo PGRN began by applying a "genotype-to-phenotype" research strategy that included, sequentially, gene resequencing, functional genomic, mechanistic and translational studies. During the present funding cycle, the Mayo PGRN has also incorporated the use of genome-wide techniques and pharmacogenomic model systems, with a special emphasis on functional mechanisms responsible for genetic effects on drug response. We have used that approach to study the pharmacogenomics ofthe endocrine therapy of breast cancer and selective serotonin reuptake inhibitor (SSRI) therapy of depression - research that grew out of the contribution of phase II enzymes to the biotransformation of the estrogens that play such an important role in breast cancer and biotransformation ofthe neurotransmitters that are central to the pathophysiology and treatment of depression. Recently, we have performed pharmacogenomic genome-wide association (GWA) studies of breast cancer, and we will soon perform similar studies of the SSRI therapy of depression. We propose to continue this genomewide focus during the next funding cycle, with both clinical and model system GWA studies of the drug therapy of breast cancer and depression, always including replication as well as functional and mechanistic studies. We also propose two "Network Resources", one designed to provide access to "Next Generation" DNA sequencing for all PGRN Centers and the other focused on pharmacogenomic ontology. In summary, the studies in this application build on Mayo PGRN strengths in DNA sequencing and functional genomics - while incorporating genome-wide techniques - to provide insight into the role of inheritance in variation in the efficacy and side effects of drugs used to treat breast cancer and depression.
Breast cancer is the most frequent cancer of women and depression is the most common major psychiatric illness. Drugs are available to treat both of these serious illnesses, but many patients fail to respond and some suffer serious adverse drug reactions. The Mayo Clinic PGRN will apply modern pharmacogenomic techniques to help make it possible to individualize the drug therapy of breast cancer and depression.
|Ho, Ada Man-Choi; Qiu, Yanyan; Jia, Yun-Fang et al. (2016) Combined Effects of Acamprosate and Escitalopram on Ethanol Consumption in Mice. Alcohol Clin Exp Res 40:1531-9|
|Tamm, Riin; MÃ¤gi, Reedik; Tremmel, Roman et al. (2016) Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: a meta-analysis of three genome-wide association studies. Clin Pharmacol Ther :|
|Ingle, James N; Xie, Fang; Ellis, Matthew J et al. (2016) Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy. Cancer Res 76:7012-7023|
|Aziz, Ayesha; Kawamoto, Kensaku; Eilbeck, Karen et al. (2016) The genomic CDS sandbox: An assessment among domain experts. J Biomed Inform 60:84-94|
|Cairns, Junmei; Ung, Choong Yong; da Rocha, Edroaldo Lummertz et al. (2016) A network-based phenotype mapping approach to identify genes that modulate drug response phenotypes. Sci Rep 6:37003|
|Chapman, Judith-Anne W; Shepherd, Lois E; Ingle, James N et al. (2016) Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27. Breast Cancer Res Treat 156:343-9|
|Caraballo, Pedro J; Hodge, Lucy S; Bielinski, Suzette J et al. (2016) Multidisciplinary model to implement pharmacogenomics at the point of care. Genet Med :|
|Deng, Min; Yang, Xu; Qin, Bo et al. (2016) Deubiquitination and Activation of AMPK by USP10. Mol Cell 61:614-24|
|Park, Jae-Hyun; Jang, Miran; Tarhan, Yunus Emre et al. (2016) Clonal expansion of antitumor TÂ cells in breast cancer correlates with response to neoadjuvant chemotherapy. Int J Oncol 49:471-8|
|Kalman, L V; AgÃºndez, Jag; Appell, M Lindqvist et al. (2016) Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. Clin Pharmacol Ther 99:172-85|
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