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,...
Published in: | Clinical and Translational Science |
---|---|
Main Authors: | , , , , , , , , , , , , , , , |
Other Authors: | |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Wiley
2021
|
Subjects: | |
Online Access: | http://dx.doi.org/10.1111/cts.12970 https://onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12970 https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cts.12970 https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12970 |
id |
crwiley:10.1111/cts.12970 |
---|---|
record_format |
openpolar |
spelling |
crwiley:10.1111/cts.12970 2024-06-09T07:47:31+00:00 Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function Fohner, Alison E. Dalton, Rachel Skagen, Kasse Jackson, Konner Claw, Katrina G. Hopkins, Scarlett E. Robinson, Renee Khan, Burhan A. Prasad, Bhagwat Schuetz, Erin G. Nickerson, Deborah A. Thornton, Timothy A. Dillard, Denise A. Boyer, Bert B. Thummel, Kenneth E. Woodahl, Erica L. National Institutes of Health 2021 http://dx.doi.org/10.1111/cts.12970 https://onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12970 https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cts.12970 https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12970 en eng Wiley http://creativecommons.org/licenses/by-nc-nd/4.0/ Clinical and Translational Science volume 14, issue 4, page 1292-1302 ISSN 1752-8054 1752-8062 journal-article 2021 crwiley https://doi.org/10.1111/cts.12970 2024-05-16T14:28:16Z 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 Wiley Online Library Anchorage Indian Yukon Clinical and Translational Science 14 4 1292 1302 |
institution |
Open Polar |
collection |
Wiley Online Library |
op_collection_id |
crwiley |
language |
English |
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. |
author2 |
National Institutes of Health |
format |
Article in Journal/Newspaper |
author |
Fohner, Alison E. Dalton, Rachel Skagen, Kasse Jackson, Konner Claw, Katrina G. Hopkins, Scarlett E. Robinson, Renee Khan, Burhan A. Prasad, Bhagwat Schuetz, Erin G. Nickerson, Deborah A. Thornton, Timothy A. Dillard, Denise A. Boyer, Bert B. Thummel, Kenneth E. Woodahl, Erica L. |
spellingShingle |
Fohner, Alison E. Dalton, Rachel Skagen, Kasse Jackson, Konner Claw, Katrina G. Hopkins, Scarlett E. Robinson, Renee Khan, Burhan A. Prasad, Bhagwat Schuetz, Erin G. Nickerson, Deborah A. Thornton, Timothy A. Dillard, Denise A. Boyer, Bert B. Thummel, Kenneth E. Woodahl, Erica L. Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function |
author_facet |
Fohner, Alison E. Dalton, Rachel Skagen, Kasse Jackson, Konner Claw, Katrina G. Hopkins, Scarlett E. Robinson, Renee Khan, Burhan A. Prasad, Bhagwat Schuetz, Erin G. Nickerson, Deborah A. Thornton, Timothy A. Dillard, Denise A. Boyer, Bert B. Thummel, Kenneth E. Woodahl, Erica L. |
author_sort |
Fohner, Alison E. |
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 |
http://dx.doi.org/10.1111/cts.12970 https://onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12970 https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cts.12970 https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1111/cts.12970 |
geographic |
Anchorage Indian Yukon |
geographic_facet |
Anchorage Indian Yukon |
genre |
Kuskokwim Alaska Yukon |
genre_facet |
Kuskokwim Alaska Yukon |
op_source |
Clinical and Translational Science volume 14, issue 4, page 1292-1302 ISSN 1752-8054 1752-8062 |
op_rights |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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_ |
1801378633725509632 |