Besides forming the foundation for my dissertation, the majority of my work with the Northwest-Alaska Pharmacogenomics Research Network has been analyses of population-level allele frequencies of pharmacogenetically important genes in underserved communities. These genes include the cytochrome P450 genes, which dominate the absorption, distribution, metabolism, and clearance of most drugs important in the treatment of disease. Variability in these genes can affect the efficacy and toxicity of a drug regimen, especially for drugs with a narrow therapeutic index.
A project investigating the population frequencies of alleles in the Cytochrome P450 genes, CYP2D6, CYP3A4, CYP3A5, and CYP2C9, in the Confederated and Salish Kootenai Tribes (CSKT) of Northwestern Montana grew from a partnership between University of Washinton, University of Montana, and the CSKT. I worked with Ken Thummel at UW and Erica Woodahl at UM to analyze the sequences of these genes in members of the CSKT and to compare the frequencies of phenotyped alleles to the frequencies of these alleles in other populations, including those in the HapMap database. From these sequences, we looked for novel variants specific to the CSKT and for differences in phenotyped allele frequencies that could inform more appropriate dosing regimens of warfarin, tacrolimus, tamoxifen in the CSKT populations. We found no common novel variants in the CSKT, but identified a difference in linkage disequilibrium pattern between variants in CYP3A4 and CYP3A5 that could lead to reduced clearance of CYP3A substrates in members of the CSKT compared to members of other populations. Skills from this work include isolating DNA from buffy coats, understanding pharmacogenetic mechanics, and calculating population allele frequencies and linkage disequilibrium.
Other projects for NWA-PGRN include investigating the ethics of research with Urban Indian communities, analyzing public health policies surrounding common genetic polymorphisms, and exploring attitudes towards recontact with research participants to ask for additional biological material for biobanking.