Pharmacogenetics of Phase II Drug Metabolizing Enzymes
Abstract (Updated, February 2013)
Pharmacogenomics is the study of the role of inheritance in variation in drug response phenotypes, phenotypes that range from life-threatening adverse drug reactions at one end of the spectrum to lack of the desired therapeutic effect of the drug at the other. Pharmacogenomic research includes studies that range from discovery to translation to clinical implementation.
The Mayo Pharmacogenomics Research Network (PGRN) Pharmacogenetics of Phase II Drug Metabolizing Enzymes (PPII) research program originally focused on genetic variation in drug metabolism, particularly Phase II, conjugation reactions. However, since the origin of the PGRN, this research program has expanded to extend across the genome and now encompasses all types of genetic variation that contribute to drug response, including the entire spectrum of genes involved in pharmacokinetic (PK) and pharmacodynamic (PD) variation.
The Mayo PGRN places special emphasis on pharmacogenomic studies of breast cancer and other cancers and on the pharmacogenomics of depression. The use of genomic data-rich cell line model systems, especially the Human Variation Panel of 300 lymphoblastoid cell lines (LCLs) from three ethnic groups, and of large clinical genome-wide association studies (GWAS) (e.g., over 14,000 DNA samples from breast cancer patients) have both proven their value in the hands of PPII investigators. This PGRN Center also always attempts to move beyond biomarkers to the functional validation of genomic SNP signals and pursuit of the mechanisms of genes identified during pharmacogenomic studies. This approach has resulted in the identification, functional validation and mechanistic study of a series of novel genes that play a role in variation in response to antineoplastic therapy. A similar approach has been taken in our studies of SSRI response during the treatment of depression, but those studies have also included pioneering work in which pharmacometabolomics has been used to inform pharmacogenomics, and the use of iPS cells from depressed patients to generate serotonergic neurons for use as a cellular model system. Clinical GWAS performed by the PPII PGRN Center have involved collaborations with several large clinical trials groups across the United States and Europe as well as a highly productive collaboration with the RIKEN Center for Genomic Medicine in Yokohama, Japan. In addition, the Mayo PPII PGRN Center has acted as a catalyst for the clinical implementation of pharmacogenomics throughout the Mayo Clinic a large, multisite academic medical center.
In summary, the Mayo Clinic NIH PPII PGRN Center is applying state-of-the-art genome-wide techniques and Next Generation DNA sequencing and the use of cellular model systems to discover novel genomic variants that influence response to the therapy of cancer and depression, always followed by functional and mechanistic pursuit of the genes identified. Another major component of PPII activities involves the systematic translation and implementation of pharmacogenomics at the bedside.
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