Pharmacogenetic Implementation in Rural and Tribal Communities

Pharmacogenetic testing has the potential to improve prescribing recommendations in a variety of clinical areas including cardiology, pain management, cancer, and mental health. Well established pharmacogenetic testing programs have been intiated in several major academic medical centers and large health systems across the US. Uptake in rural, community based facilities has been slow, however, threatening to exacerbate healthcare disparities for rural and tribal populations. We are the first to begin pharmacogenetic testing implementation in Montana, with a focus on equitable access for underserved patients.

Assessment of barriers and facilitators to pharmacogenetic testing implementation in rural and tribal communities

We assessed the feasibility and readiness for pharmacogenetic testing implementation at three early adopter sites in Montana, Shodair Children's Hospital in Helena, Partnership Health Center in Missoula, and the Confederated Salish and Kootenai Tribal Health Department in St. Ignatius. Through this research, we determined barriers and facilitators to pharmacogenetic testing unique to these populations as well as assessed the use of using telehealth as a means to equitably deliver pharmacogenetics services. We used these findings to begin a pilot pharmacogenetic testing program primarily delivered via telehealth modalities. This work was supported by the National Institutes of Health through the following research grants: P01GM116691 and R01HG009500.

A pharmacogenetic testing implementation pilot with Shodair Children's Hospital

Children living in rural areas experience alarmingly high rates of depression and suicide, due in part to limited access to mental health services. Pharmacogenetic testing in these communities is even more inaccessible. We partnered with Shodair Children's Hospital in Helena, the leading provider of pediatric psychiatry in Montana, to address inequities by implementing a pharmacogenetics testing service at the University of Montana. We identified study endpoints of interest to research and clinical stakeholders, developed satisfaction surveys for patients and providers, and generated educational materials.We then launched a pharmacogenetics implementation program, based at Shodair, serving rural and underserved patients, using telehealth technologies to advance accessibility. We also developed a video to provide pharmacogenetics education to patients (see below). Our goal is to provide a centralized hub for delivery of pharmacogenetics statewide and serve as a model for other areas serving geographically dispersed populations. 

Precision Medicine Research with American Indian and Alaska Native Populations

An important focus of the research in the Woodahl laboratory is conducting precision medicine and pharmacogenomics research with American Indian and Alaska Native (AIAN) people to address health disparities using a community-based participatory research approach. Precision medicine is an approach for the treatment and prevention of disease that takes into account patient differences in their genetic make-up, environment, and lifestyle. We have developed community-academic partnerships across the Pacific Northwest and Alaska, including Montana, Alaska, Oregon, and Washington. In Montana, we have established a partnership between the University of Montana and the Confederated Salish and Kootenai Tribes (CSKT) on the Flathead Reservation. Through this partnership, the Woodahl laboratory published the first comprehensive resequencing of the major cytochrome P450s (CYPs) genes in an American Indian population – CYP2D6, CYP3A4, CYP3A5, and CYP2C9 – and identified a unique CYP3A haplotype that may be an important contributor to interindividual variability in drug metabolism. The research group has also conducted qualitative research with healthcare providers about the clinical feasibility of implementing pharmacogenomics tests in rural and tribal health care settings; this study makes it clear that pharmacogenomic and precision medicine research agendas must include implementation science research in diverse practice settings outside large metropolitan areas. Our community-academic partnership is based on more than 10 years of building relationships, trust, and community engagement into the research process, including the formation of a community advisory board. We are in a unique position of integrating community-based participatory research with basic and translational precision medicine research to lay the groundwork for implementation of precision medicine in AIAN populations. Our research is part of the Northwest-Alaska Pharmacogenomics Research Network (NWA-PGRN), whose goals are to engage indigenous populations in precision medicine research (1U01GM092676 and P01GM116691).

Tobacco cessation and pharmacogenomic predictors in American Indian populations

Nicotine is metabolized by the drug-metabolizing enzyme CYP2A6 and differences in this genotype have been associated with variation in tobacco exposure, smoking cessation, and lung cancer risk. American Indian (AI) populations studied to date have the highest nicotine metabolite ratio reported compared to other populations and have unique allele frequencies and novel variation within the CYP2A6 gene. However, AI populations are often left out of pharmacogenomic research and therefore it is important that they are included so that clinical tools that come from this research will be available to them. We are conducting a survey with the Confederated Salish and Kootenai Tribes (CSKT) members and descendants to assess their views about pharmacogenetic research being used as a tool to guide personalized treatment for tobacco cessation. By continuing these conversations about pharmacogenetic research in tobacco cessation, future research areas may be better guided and help inform Tribal Health providers about which tobacco cessation approaches may be the best for their patients. This study is part of a precision medicine research project between the CSKT Tribal Health Department and the University of Montana Skaggs School of Pharmacy that was established in 2007. Funded by the NHGRI Genomic Innovator Award (Grant #R35HG011319).

Dietary and genomic predictors of anti-platelet response

Both genetic and dietary factors contribute to interindividual differences in the basal function of platelets and their response to antiplatelet therapy such as aspirin. Antiplatelet therapy is the standard of care for men and women at risk of thromboembolic events. The goal of our research is to determine the extent to which genetic variation and dietary w-3 polyunsaturated fatty acid consumption modifies platelet structure, function, and antiplatelet drug response; and to apply this knowledge towards improving therapeutic outcomes in underserved American Indian and Alaska Native populations receiving antiplatelet therapy. Funded by NIH grant P01GM116691.

Genetic and seasonal variability of vitamin D

Vitamin D is obtained through synthesis in the skin following exposure to ultraviolet B radiation and dietary intake. There is a growing concern worldwide about the development of chronic diseases associated with vitamin D deficiency, including osteoporosis, depression, diabetes, cardiovascular diseases, autoimmune disorders, and cancer. Vitamin D deficiency is of particular concern to populations living in northern latitudes where there is reduced sunlight exposure in winter months. The goal of our research is to understand how diet, genetics, and sunlight contribute to vitamin D homeostasis and optimal health in American Indian people. We focus on interindividual variability in vitamin D deficiency, as measured by the major circulating metabolite of vitamin D, 25-hydroxyvitamin D₃ [25(OH)D₃]. Funded by NIH grant U54GM115371.

Community-engaged research toward precision medicine with American Indian and Alaska Native people

While precision medicine can potentially benefit people of all ethnicities, most research studies have been limited to people of European descent. We seek to build on existing community-university partnerships with tribal communities in Alaska and Montana to advance policy approaches to support precision medicine research with American Indian and Alaska Native people. The project will address three complex and important challenges: (1) how precision medicine research may benefit tribal people and how research aligns with tribal health priorities; (2) how to develop flexible, community-responsive approaches to the return of research results to tribal participants and their communities; and (3) how to address issues of data stewardship that support the full participation of tribal communities in research. Funded by NIH grant R01HG009500.

Tamoxifen pharmacogenomics

Tamoxifen is a selective estrogen receptor modulator used to reduce the risk of recurrence of estrogen-positive breast cancer. Tamoxifen is bioactivated to its active metabolites primarily by cytochrome P450 (CYP) drug-metabolizing enzymes. CYP2D6 is the key enzyme involved in tamoxifen bioactivation with CYP3A4, CYP3A5, and CYP2C9 also contributing. We conducted the first pharmacogenetic study in American Indian and Alaska Native women to examine the association of variation in these CYP genes and tamoxifen biotransformation. We found that CYP2D6 variation was significantly associated with plasma concentrations of endoxifen and 4-hydroxytamoxifen, tamoxifen’s principal active metabolites. Women with decreased CYP2D6 activity have significantly lower circulating levels of the active metabolites, which other researchers have shown leads to an increased risk of breast cancer recurrence. As a result, these patients may benefit from alternative prescribing strategies before initiating anti-estrogenic therapy. We have identified that this occurs in ~4% of women treated at the Southcentral Foundation in Alaska and in ~9% of women from the Confederated Salish and Kootenai Tribes in Montana. Our research shows the importance of identifying patients unlikely to respond prior to initiating tamoxifen therapy so that prescribing choices can optimize delivery of precision medicine. Funded by NIH grants 1U01GM092676 and P01GM116691.

Interindividual variation in pharmacokinetics and pharmacodynamics

Drug-metabolizing enzymes

Cytochrome P450 (CYP) enzymes are the largest contributor to phase I drug metabolism and a variation in the genes that encode these enzymes are a major source of interindividual variability in drug response and toxicity. We have a particular focus on two CYP enzymes: CYP2D6 and CYP3A4. CYP2D6 is responsible for the metabolism of 25% of all clinically used drugs from a wide range of drug classes. There is a large amount of genetic variability in the CYP2D6 gene, including many single nucleotide variants, indels, and structural variation. Most currently-available clinical genotyping platforms are unable to capture the full range of variation seen in CYP2D6, resulting in potentially incorrect predictions about an individual’s CYP2D6 activity and clinical consequences such as adverse effects or treatment failure. We are focused on improving the accuracy of CYP2D6 pharmacogenetic tests through the use of targeted next generation sequencing coupled with a novel bioinformatics tool. This approach allows interrogation of complex diplotypes without the limitations imposed by targeted genotyping panels. See video below for an overview of this work. We also developed a convolutional neural network, Hubble.2D6, as a transfer learning model to predict function of CYP2D6 haplotypes in silico.

CYP3A4 metabolizes a wide variety of substrates and is responsible for the metabolism of ~50% of clinically used drugs. There is extensive variability in CYP3A4 activity that is influenced by multiple factors, including hormonal and xenobiotic regulation and genetic variation. We identified a unique CYP3A diplotype in the Confederated Salish and Kootenai Tribes that may be an important contributor to interindividual variability in drug metabolism in this population. In a follow-up study, we characterized the functional consequence of this diplotype, which contains the CYP3A4*1G allele (now known as CYP3A4*36.002). We are also interested in the role of vitamin D in the regulation of CYP3A4, especially whether the regulation varies seasonally between the winter and summer months. Funded by NIH grants 1U01GM092676 and P01GM116691.

Drug transporters

P-glycoprotein (P-gp) is the most well studied drug transporter in the human body. P-gp transports compounds from many different therapeutic areas as well as other xenobiotic and is expressed throughout the body in tissues important in absorption, distribution, and elimination. We use membrane-based, cell-based, and in vivo models to characterize P-gp transport of a variety of xenobiotics including neurotoxic pesticides (paraquat and others), food additives, and pharmaceuticals (e.g. anticancer agents, HIV protease inhibitors, and immunosuppressive agents).