PPII Profile

Goals

This project represents a continuation of the Mayo Clinic Pharmacogenomics Research Network (PGRN) Research Program "Pharmacogenetics of Phase II Drug Metabolizing Enzymes". The Mayo PGRN is an integrated, multidisciplinary, multi-institutional research effort that is itself integrated within the overall NIH-sponsored multi-institution PGRN. The Mayo PGRN was based initially on a decades-long focus at Mayo on studies of the pharmacogenetics and pharmacogenomics of phase II (conjugating) drug-metabolizing enzymes. Those same enzymes also catalyze the metabolism of hormones such as estrogens and of monoamine neurotransmitters. However, that “foundation” has now been expanded to include the application of a series of genome-wide techniques and model systems with a focus on two major areas of therapeutics — the treatment of breast cancer patients with aromatase inhibitors and the treatment of depressed patients with selective serotonin reuptake inhibitors (SSRIs).

Progress

The sequences of a large number of genes encoding “phase II” enzymes that catalyze the conjugation of drugs, neurotransmitters and hormones were determined during the initial funding period for this project. Functional genomic studies of nonsynonymous coding single nucleotide polymorphism (cSNPs) were performed for many of these genes. One key observation made was that the most common mechanism by which nonsynonymous cSNPs alter protein function involves a decrease in protein quantity — most often as a result of accelerated proteasome-dependent degradation. The Mayo PGRN also reported that the clinically important TPMT*3A variant allele undergoes aggresome formation as a mechanism by which function is altered — a first in pharmacogenetics. In addition to gene resequencing and functional genomic studies, the Mayo PGRN also “translated” its findings to apply them to studies of the drug therapy of inflammatory bowel disease and childhood leukemia as well as the pathophysiology of breast cancer. These observations have now been expanded to include the application of genome-wide techniques to model systems such as yeast gene deletion libraries and “Human Variation Panel” lymphoblastoid cell lines to study the pharmacogenomics of drug response phenotypes. In addition, genome-wide association studies are being applied to clinical samples obtained from patients treated with aromatase inhibitors and SSRIs.

Experimental plans

The Mayo PGRN — as described above — has most often utilized a genotype-to-phenotype research strategy that begins by resequencing genes which encode proteins of interest, followed by characterization of the functional effects of genetic polymorphisms present in those genes — with a special emphasis on mechanisms by which those polymorphisms influence function. That approach is being continued and expanded — with a continued emphasis on providing genetic polymorphism, functional genomic and mechanistic data to the pharmacogenetic and pharmacogenomic research community — but also extending this line of research to include studies of the pharmacogenomics of the aromatase inhibitor anastrozole and the SSRI escitalopram. As pointed out previously, these studies increasingly take advantage of high throughput genome-wide techniques and genomic-model systems. The Mayo PGRN clinical pharmacogenomic studies are based directly on a long history of pharmacogenomic studies of the role of phase II enzymes in the conjugation of estrogens, which are synthesized by aromatase, and the conjugation of monoamine neurotransmitters, whose function is altered by SSRIs such as escitalopram. All pharmacogenomic information obtained as a result of the research conducted by the Mayo PGRN will be rapidly deposited in the NIH-sponsored PharmGKB Knowledge Base.