Genetic and environmental associations with disease risk and drug response in Alaska Native people, and a responsive justice approach to reconciling statistical and ethical research demands.
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Genetic research with diverse and underserved communities is important for expanding the benefits of genetic discoveries and their application to personalized medicine. In partnership with Alaska Native communities, we identified and characterized novel and known variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, 5 genes known to affect warfarin disposition and response, in 350 Yup’ik people and 365 customer-owners of Southcentral Foundation. Through resequencing and targeted genotyping, we identified two common novel variants M1L and N218I in CYP2C9 and high frequencies of the VKORC1 haplotype (-1639G>A and 1173C>T) that are expected to result in increased warfarin sensitivity. We also observed high frequencies of CYP4F2*3, which may increase vitamin K conservation and necessitate a higher warfarin dose to achieve the desired anticoagulation effect. Individual patient needs will depend on a complex mixture of genetic traits. Because of seasonal variation in sunlight exposure, vitamin D deficiency is a concern for people living in circumpolar regions. We characterized 25(OH)D3 concentrations in 743 Yup’ik people living in the Yukon Kuskokwim delta of southwestern Alaska and identified sources of inter-individual variability, including season of sample collection, genetic variation in CYP2R1 and DHCR7, age, gender, body mass index, the degree of consumption of the traditional diet, and inland or coastal geography of the community. Yup’ik participants on average had adequate concentrations of 25(OH)D3 (31.1 +/- 0.9 ng/mL), but a younger age (< 33 years) was significantly associated with lower concentration of 25(OH)D3 (24.5 ng/mL compared to 37.5 ng/mL for ages > 33 years), lower levels of a biomarker of traditional food consumption, and greater fluctuation with changes in sunlight exposure. Younger Yup’ik participants may be at increased risk for adverse outcomes associated with vitamin D deficiency, especially during seasons of low sunlight exposure. Finally, in genetic epidemiology research, genome-wide markers or pedigree information is used to adjust for population substructure and prevent confounding of results. Population substructure and the concerns of communities with respect to the methods used to adjust for it are described. A responsive justice framework is suggested as a tool to approach these conflicting demands of research, presenting as an example the stratification of participants by self-identified ancestral language group to approximate the statistical adjustments needed for population stratification.