Pharmacogenomic approaches to drug metabolism in American Indian/Alaska Native People

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Summary Pharmacogenetic testing is expected to enhance drug safety and efficacy while improving clinical outcomes by tailoring treatment regimens to the individual. Key to maximizing benefits of this approach will be comprehensive characterization of genetic variation that modulates drug absorption, distribution, metabolism and excretion, drug target interaction and pharmacological response across populations. Significant advances in cataloguing pharmacogenomic profiles from major populations of the world have aided clinical applications but have largely excluded historically marginalized populations and small, geographically isolated populations, including American Indian and Alaska Native (AIAN) people. These populations continue to be underrepresented in genomic research for a variety of reasons: lack of community engagement, historical mistrust, and geographical remoteness. Recent genetic studies by the Northwest Alaska Pharmacogenetic Research Network (NWA-PGRN)—a center with multiple institutional and tribal partners—have shown that AIAN people carry variants in pharmacogenes that are both novel and common, have allele frequencies of known variants that are different than other ethnic or racial groups, and display high inter-tribal variability as well. To broaden this research, we propose to leverage the lessons learned and build on research from the NWA-PGRN to understand inter-individual variation in drug responses and provide novel indicators and guidelines for implementing personalized medicine in AIAN communities. Our overall goal is to fill this knowledge gap through characterizing genomic variation of pharmacogenes in a wide range of AIAN populations using an ethical and community-engaged framework that focuses on developing and deepening research partnerships with AIAN communities. We also seek to investigate the relationships between genotype-phenotype of novel variants using in silico prediction and in vivo functional assays. This work will create a general model for genomic research that engages communities in the research plan throughout the research project (from start to completion and beyond) and will serve as a foundational way to shift the research framework in genomics.