Overview

Mayo's participation in the Pharmacogenomics Research Network is building on that foundation, taking advantage of the convergence of advances in molecular pharmacogenetics and human genomics to determine and make available to the biomedical research community information with regard to common, single nucleotide polymorphisms (SNPs) as well as insertion/deletion events within genes that encode proteins that catalyze phase II pathways of drug metabolism in humans -- with special emphasis on those enzymes that catalyze methyl and sulfate conjugation.

Mayo is going beyond merely rapidly providing data on common sequence variations in genes for phase II drug-metabolizing enzymes to also include studies designed to determine the functional significance of inherited alterations in encoded amino acid sequence that result from these common genetic polymorphisms. Since functionally significant variations in amino acid sequence can potentially alter either the catalytic properties of an enzyme or, as has been found to be increasingly common, they can alter the level of enzyme protein, functional genomic studies are focusing on these two possibilities. 

Additionally, Mayo is including homology-based structural modeling for selected proteins, attempting to test the hypothesis that it may be possible to predict the functional consequences of inherited alteration in encoded amino acid sequence for phase II enzymes. This integrated approach combines determinations of inherited nucleotide sequence variation, the functional consequences of gene sequence variation that alters encoded amino acids, homology-based structural modeling, and finally the evaluation of high throughput analytical techniques for SNP and insertion/deletion detection that could potentially be applied in a clinical research setting. All this can make it possible to apply pharmacogenetic information to test medically relevant hypotheses with regard to individual variations in drug response. 

In summary, a comprehensive, integrated program of pharmacogenomic and pharmacogenetic studies of phase II drug-metabolizing enzymes, with special emphasis on methyltransferase and sulfotransferase enzymes, is being undertaken.