Genetic and seasonal determinants of vitamin D status in Confederated Salish and Kootenai Tribes (CSKT) participants

Authors' Names

Jack W. Staples, University of Montana, MissoulaFollow
Kathleen M. George, University of Montana, MissoulaFollow
Rachel Dalton, University of Montana, MissoulaFollow
Erin E. Ellerbeck, University of Montana, MissoulaFollow
Genevieve Krause, University of Montana, MissoulaFollow
Tianna Lietch, University of Montana, MissoulaFollow
Theresa Aliwarga, University of Washington, SeattleFollow
Matthew G. McDonald, University of Washington, SeattleFollow
Brian Phillips, University of Washington, SeattleFollow
LeeAnna I. Muzquiz, Tribal Health Department, Confederated Salish and Kootenai Tribes, St. IgnatiusFollow
Deborah A. Nickerson, University of Washington, SeattleFollow
Timothy A. Thornton, University of Washington, SeattleFollow
Kenneth E. Thummel, University of Washington, SeattleFollow
Erica L. Woodahl, University of Montana, MissoulaFollow

Presentation Type

Poster Presentation

Category

STEM (science, technology, engineering, mathematics)

Abstract/Artist Statement

Background: Vitamin D is a hormone produced in the skin upon ultraviolet B (UVB) radiation. Vitamin D is a crucial regulator of calcium and phosphate levels for bone mineralization and other physiological roles. Vitamin D levels vary globally in human populations due to genetics, geography, and other demographic factors. It is estimated that 20-85 % of the variability in vitamin D levels is driven by genetic variation. To improve our understanding of contributors to vitamin D levels, we conducted a candidate-gene study in partnership with the Confederated Salish and Kootenai Tribes (CSKT).

Methods: We recruited 472 CSKT study participants on the Flathead Reservation in Montana. Demographic factors included age, BMI, and gender (185 male and 287 female; ≥ 18 years old). Genomic DNA and plasma were isolated from whole blood. We sequenced 14 vitamin D regulatory candidate genes: CASR, CUBN, CYP2R1, CYP3A4,CYP24A1, CYP27B1, DHCR7, GC, RXRA, RXRB, RXRG, SULT2A1, UGT1A4, and VDR. We also measured plasma levels of vitamin D and vitamin D metabolites by liquid chromatography/mass-spectrometry (LC/MS), including the clinical marker of vitamin D status, 25-hydroxyvitamin D₃ [25(OH)D₃]. We tested demographic factors as well as common and rare genetic variants for statistical associations with vitamin D levels using bioinformatics software and R statistical programming language code.

Results: We identified 7,370 total genetic variants with 8% (n = 585) of them being novel. We identified 60 genetic variants that may be of clinical significance (disease associated or predicted to influence medication response). Vitamin D levels were below sufficiency [25(OH)D₃ + 25(OH)D₂ levels < 20 ng/mL] in 56 % of CSKT participants across the year. We observed seasonal vitamin D and metabolite level fluctuations in a seasonal, sinusoidal statistical model with peak concentrations in June – August and trough concentrations in December – February. In linear regression analysis, we found that age, BMI, season, and 5 variants in CUBN and CYP3A4 were significantly associated with 25(OH)D₃ concentration (p-value< 0.05). In logistic regression, we found that 4 variants in CUBN, CYP3A4, and UGT1A4 were associated with 25(OH)D sufficiency status [25(OH)D₃ + 25(OH)D₂ levels of 20 ng/mL] (p-value< 0.05). Multivariate linear regression analysis revealed that genetic variation alone explained ~13% of the variability in 25(OH)D₃ concentration in CSKT participants. Genetic variation and environmental factors together explained ~23 % of the variability in 25(OH)D₃ concentration in CSKT participants. It is likely that genetic variation in additional genes and other environmental factors (e.g., dietary vitamin D intake) that were not included in this study explain the remaining variability in 25(OH)D₃ concentration.

Conclusion: This research addresses the need for increased inclusion of American Indian and Alaska Natives in precision medicine health research. We are the first to describe the contribution of season and genetics to vitamin D levels in an American Indian population. Our next steps will be to use these findings to perform mechanistic studies and develop interventional strategies for the CSKT people.

Mentor Name

Erica Woodahl

Personal Statement

The lack of inclusion of American Indian and Alaska Native communities such as the Confederated Salish and Kootenai Tribes (CSKT) on the Flathead Reservation in Montana in precision medicine and pharmacogenomics research is a current healthcare disparity that needs to be addressed. In Montana, healthcare disparities are striking in tribal and rural communities. Since there is currently little or no precision medicine and pharmacogenomics research knowledge available for these populations, they are at risk of not benefiting from health innovations that arise from this research, potentially exacerbating healthcare disparities. By increasing participation of these groups in precision medicine research often, researchers and doctors can identify unique individual characteristics (e.g., genes, environment, and lifestyle) that influence how they respond to medications and use this knowledge to improve healthcare for these underserved communities. This work provides the value of increased inclusion of the CSKT people, an underserved and understudied population, in precision medicine research. In the long term, this research with the CSKT will generate novel data on seasonal vitamin D levels and associations with genetic variation in genes of the vitamin D endocrine system. The data from this research will provide knowledge to the field of precision medicine and pharmacogenomics that can be potentially be used to optimize clinical care in CSKT people.