Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX
Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential ben...
Published in: | Pharmacogenetics and Genomics |
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Language: | English |
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Lippincott Williams & Wilkins
2015
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Online Access: | https://espace.library.uq.edu.au/view/UQ:31f467b |
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ftunivqespace:oai:espace.library.uq.edu.au:UQ:31f467b 2023-05-15T17:05:40+02:00 Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX Fohner, Alison E. Robinson, Renee Yracheta, Joseph Dillard, Denise A. Schilling, Brian Khan, Burhan Hopkins, Scarlett Boyer, Bert B. Black, Jynene Wiener, Howard Tiwari, Hemant K. Gordon, Adam Nickerson, Deborah Tsai, Jesse M. Farin, Federico M. Thornton, Timothy A. Rettie, Allan E. Thummel, Kenneth E. 2015-07-01 https://espace.library.uq.edu.au/view/UQ:31f467b eng eng Lippincott Williams & Wilkins doi:10.1097/FPC.0000000000000143 issn:1744-6872 issn:1744-6880 orcid:0000-0001-6695-4366 U01 GM092676 Atrial-Fibrillation Pharmacogenetic Research Cytochrome P4502C9 Drug Variants Stroke Polymorphisms Genotypes Mortality Mutation 1311 Genetics 1312 Molecular Biology 1313 Molecular Medicine 2716 Genetics (clinical) Journal Article 2015 ftunivqespace https://doi.org/10.1097/FPC.0000000000000143 2020-10-06T02:29:22Z Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. Methods We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). Results We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G > A and 1173C > T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Conclusion Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska. Article in Journal/Newspaper Kuskokwim Yup'ik Alaska Yukon The University of Queensland: UQ eSpace Anchorage Indian Yukon Pharmacogenetics and Genomics 25 7 343 353 |
institution |
Open Polar |
collection |
The University of Queensland: UQ eSpace |
op_collection_id |
ftunivqespace |
language |
English |
topic |
Atrial-Fibrillation Pharmacogenetic Research Cytochrome P4502C9 Drug Variants Stroke Polymorphisms Genotypes Mortality Mutation 1311 Genetics 1312 Molecular Biology 1313 Molecular Medicine 2716 Genetics (clinical) |
spellingShingle |
Atrial-Fibrillation Pharmacogenetic Research Cytochrome P4502C9 Drug Variants Stroke Polymorphisms Genotypes Mortality Mutation 1311 Genetics 1312 Molecular Biology 1313 Molecular Medicine 2716 Genetics (clinical) Fohner, Alison E. Robinson, Renee Yracheta, Joseph Dillard, Denise A. Schilling, Brian Khan, Burhan Hopkins, Scarlett Boyer, Bert B. Black, Jynene Wiener, Howard Tiwari, Hemant K. Gordon, Adam Nickerson, Deborah Tsai, Jesse M. Farin, Federico M. Thornton, Timothy A. Rettie, Allan E. Thummel, Kenneth E. Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX |
topic_facet |
Atrial-Fibrillation Pharmacogenetic Research Cytochrome P4502C9 Drug Variants Stroke Polymorphisms Genotypes Mortality Mutation 1311 Genetics 1312 Molecular Biology 1313 Molecular Medicine 2716 Genetics (clinical) |
description |
Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. Methods We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). Results We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G > A and 1173C > T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Conclusion Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska. |
format |
Article in Journal/Newspaper |
author |
Fohner, Alison E. Robinson, Renee Yracheta, Joseph Dillard, Denise A. Schilling, Brian Khan, Burhan Hopkins, Scarlett Boyer, Bert B. Black, Jynene Wiener, Howard Tiwari, Hemant K. Gordon, Adam Nickerson, Deborah Tsai, Jesse M. Farin, Federico M. Thornton, Timothy A. Rettie, Allan E. Thummel, Kenneth E. |
author_facet |
Fohner, Alison E. Robinson, Renee Yracheta, Joseph Dillard, Denise A. Schilling, Brian Khan, Burhan Hopkins, Scarlett Boyer, Bert B. Black, Jynene Wiener, Howard Tiwari, Hemant K. Gordon, Adam Nickerson, Deborah Tsai, Jesse M. Farin, Federico M. Thornton, Timothy A. Rettie, Allan E. Thummel, Kenneth E. |
author_sort |
Fohner, Alison E. |
title |
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX |
title_short |
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX |
title_full |
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX |
title_fullStr |
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX |
title_full_unstemmed |
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX |
title_sort |
variation in genes controlling warfarin disposition and response in american indian and alaska native people: cyp2c9, vkorc1, cyp4f2, cyp4f11, ggcx |
publisher |
Lippincott Williams & Wilkins |
publishDate |
2015 |
url |
https://espace.library.uq.edu.au/view/UQ:31f467b |
geographic |
Anchorage Indian Yukon |
geographic_facet |
Anchorage Indian Yukon |
genre |
Kuskokwim Yup'ik Alaska Yukon |
genre_facet |
Kuskokwim Yup'ik Alaska Yukon |
op_relation |
doi:10.1097/FPC.0000000000000143 issn:1744-6872 issn:1744-6880 orcid:0000-0001-6695-4366 U01 GM092676 |
op_doi |
https://doi.org/10.1097/FPC.0000000000000143 |
container_title |
Pharmacogenetics and Genomics |
container_volume |
25 |
container_issue |
7 |
container_start_page |
343 |
op_container_end_page |
353 |
_version_ |
1766060364896665600 |