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,...
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Online Access: | https://doi.org/10.1111/cts.12970 https://doaj.org/article/18c815b78eaf46c482f67ddc2280dfe6 |
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ftdoajarticles:oai:doaj.org/article:18c815b78eaf46c482f67ddc2280dfe6 2023-05-15T17:05:40+02:00 Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function Alison E. Fohner Rachel Dalton Kasse Skagen Konner Jackson Katrina G. Claw Scarlett E. Hopkins Renee Robinson Burhan A. Khan Bhagwat Prasad Erin G. Schuetz Deborah A. Nickerson Timothy A. Thornton Denise A. Dillard Bert B. Boyer Kenneth E. Thummel Erica L. Woodahl 2021-07-01T00:00:00Z https://doi.org/10.1111/cts.12970 https://doaj.org/article/18c815b78eaf46c482f67ddc2280dfe6 EN eng Wiley https://doi.org/10.1111/cts.12970 https://doaj.org/toc/1752-8054 https://doaj.org/toc/1752-8062 1752-8062 1752-8054 doi:10.1111/cts.12970 https://doaj.org/article/18c815b78eaf46c482f67ddc2280dfe6 Clinical and Translational Science, Vol 14, Iss 4, Pp 1292-1302 (2021) Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1111/cts.12970 2022-12-31T13:16:44Z 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’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’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. Article in Journal/Newspaper Kuskokwim Alaska Yukon Directory of Open Access Journals: DOAJ Articles Anchorage Indian Yukon Clinical and Translational Science 14 4 1292 1302 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 |
spellingShingle |
Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Alison E. Fohner Rachel Dalton Kasse Skagen Konner Jackson Katrina G. Claw Scarlett E. Hopkins Renee Robinson Burhan A. Khan Bhagwat Prasad Erin G. Schuetz Deborah A. Nickerson Timothy A. Thornton Denise A. Dillard Bert B. Boyer Kenneth E. Thummel Erica L. Woodahl Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
topic_facet |
Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 |
description |
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’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’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. |
format |
Article in Journal/Newspaper |
author |
Alison E. Fohner Rachel Dalton Kasse Skagen Konner Jackson Katrina G. Claw Scarlett E. Hopkins Renee Robinson Burhan A. Khan Bhagwat Prasad Erin G. Schuetz Deborah A. Nickerson Timothy A. Thornton Denise A. Dillard Bert B. Boyer Kenneth E. Thummel Erica L. Woodahl |
author_facet |
Alison E. Fohner Rachel Dalton Kasse Skagen Konner Jackson Katrina G. Claw Scarlett E. Hopkins Renee Robinson Burhan A. Khan Bhagwat Prasad Erin G. Schuetz Deborah A. Nickerson Timothy A. Thornton Denise A. Dillard Bert B. Boyer Kenneth E. Thummel Erica L. Woodahl |
author_sort |
Alison E. Fohner |
title |
Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
title_short |
Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
title_full |
Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
title_fullStr |
Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
title_full_unstemmed |
Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
title_sort |
characterization of cyp3a pharmacogenetic variation in american indian and alaska native communities, targeting cyp3a4*1g allele function |
publisher |
Wiley |
publishDate |
2021 |
url |
https://doi.org/10.1111/cts.12970 https://doaj.org/article/18c815b78eaf46c482f67ddc2280dfe6 |
geographic |
Anchorage Indian Yukon |
geographic_facet |
Anchorage Indian Yukon |
genre |
Kuskokwim Alaska Yukon |
genre_facet |
Kuskokwim Alaska Yukon |
op_source |
Clinical and Translational Science, Vol 14, Iss 4, Pp 1292-1302 (2021) |
op_relation |
https://doi.org/10.1111/cts.12970 https://doaj.org/toc/1752-8054 https://doaj.org/toc/1752-8062 1752-8062 1752-8054 doi:10.1111/cts.12970 https://doaj.org/article/18c815b78eaf46c482f67ddc2280dfe6 |
op_doi |
https://doi.org/10.1111/cts.12970 |
container_title |
Clinical and Translational Science |
container_volume |
14 |
container_issue |
4 |
container_start_page |
1292 |
op_container_end_page |
1302 |
_version_ |
1766060361743597568 |