@article{d22dd68e6c2149a587c4dfb9b8f7aeb2,
title = "Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function",
abstract = "The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup{\textquoteright}ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4β-vitamin D hydroxylation activity in Yup{\textquoteright}ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele—coupled with low frequency of the functional CYP3A5*1 variant—may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.",
author = "Fohner, {Alison E.} and Rachel Dalton and Kasse Skagen and Konner Jackson and Claw, {Katrina G.} and Hopkins, {Scarlett E.} and Renee Robinson and Khan, {Burhan A.} and Bhagwat Prasad and Schuetz, {Erin G.} and Nickerson, {Deborah A.} and Thornton, {Timothy A.} and Dillard, {Denise A.} and Boyer, {Bert B.} and Thummel, {Kenneth E.} and Woodahl, {Erica L.}",
note = "Funding Information: This work was supported by NIH grant funding to the Northwest Alaska - Pharmacogenomics Research Network (NWA-PGRN) (U01GM092676 and P01GM116691), R01GM63666, and the EDGE center grant (P30ES007033). The authors thank all of the recruitment personnel in the YK Delta, research staff at SCF, and Barbara Kavanaugh, Program Manager for the Northwest Alaska – Pharmacogenomics Research Network (NWA-PGRN), for directing programmatic collaborations. We would also like to thank Patricia L. Stapleton and Jesse M. Tsai in the Functional Genomics Laboratory at the University of Washington for performing the genotyping assay. This work was supported by National Institutes of Health (NIH) grant funding to the NWA-PGRN (U01GM092676 and P01GM116691), R01GM63666, and the EDGE center grant (P30ES007033). Finally, the authors would like to express their deep appreciation to all of the American Indian and Alaska Native people who participated in this research study and the communities in which they live. Funding Information: The authors thank all of the recruitment personnel in the YK Delta, research staff at SCF, and Barbara Kavanaugh, Program Manager for the Northwest Alaska – Pharmacogenomics Research Network (NWA‐PGRN), for directing programmatic collaborations. We would also like to thank Patricia L. Stapleton and Jesse M. Tsai in the Functional Genomics Laboratory at the University of Washington for performing the genotyping assay. This work was supported by National Institutes of Health (NIH) grant funding to the NWA‐PGRN (U01GM092676 and P01GM116691), R01GM63666, and the EDGE center grant (P30ES007033). Finally, the authors would like to express their deep appreciation to all of the American Indian and Alaska Native people who participated in this research study and the communities in which they live. Funding Information: This work was supported by NIH grant funding to the Northwest Alaska ‐ Pharmacogenomics Research Network (NWA‐PGRN) (U01GM092676 and P01GM116691), R01GM63666, and the EDGE center grant (P30ES007033). Publisher Copyright: {\textcopyright} 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.",
year = "2021",
month = jul,
doi = "10.1111/cts.12970",
language = "English (US)",
volume = "14",
pages = "1292--1302",
journal = "Clinical and Translational Science",
issn = "1752-8054",
publisher = "Wiley-Blackwell",
number = "4",
}