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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'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.

SUBMITTER: Fohner AE

PROVIDER: S-EPMC8301563 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

Fohner Alison E AE Dalton Rachel R Skagen Kasse K Jackson Konner K Claw Katrina G KG Hopkins Scarlett E SE Robinson Renee R Khan Burhan A BA Prasad Bhagwat B Schuetz Erin G EG Nickerson Deborah A DA Thornton Timothy A TA Dillard Denise A DA Boyer Bert B BB Thummel Kenneth E KE Woodahl Erica L EL

Clinical and translational science 20210127 4

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 it ...[more]

PMID: 33503331

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Project description:IntroductionOpioid-related overdose mortality rates have increased sharply in the U.S. over the past two decades, and inequities across racial and ethnic groups have been documented. Opioid-related overdose trends among American Indian and Alaska Natives require further quantification and assessment.MethodsObservational, U.S. population-based registry data on opioid-related overdose mortality between 1999 and 2021 were extracted in 2023 using ICD-10 codes from the U.S. Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research multiple cause of death file by race, Hispanic ethnicity, sex, and age. Segmented time series analyses were conducted to estimate opioid-related overdose mortality growth rates among the American Indian and Alaska Native population between 1999 and 2021. Analyses were performed in 2023.ResultsTwo distinct time segments revealed significantly different opioid-related overdose mortality growth rates within the overall American Indian and Alaska Native population, from 0.36 per 100,000 (95% CI=0.32, 0.41) between 1999 and 2019 to 6.5 (95% CI=5.7, 7.31) between 2019 and 2021, with the most pronounced increase among those aged 24-44 years. Similar patterns were observed within the American Indian and Alaska Native population with Hispanic ethnicity, but the estimated growth rates were generally steeper across most age groups than across the overall American Indian and Alaska Native population. Patterns of opioid-related overdose mortality growth rates were similar between American Indian and Alaska Native females and males between 2019 and 2021.ConclusionsSharp increases in opioid-related overdose mortality rates among American Indian and Alaska Native communities are evident by age and Hispanic ethnicity, highlighting the need for culturally sensitive fatal opioid-related overdose prevention, opioid use disorder treatment, and harm-reduction efforts. Future research should aim to understand the underlying factors contributing to these high mortality rates and employ interventions that leverage the strengths of American Indian and Alaska Native culture, including the strong sense of community.

Project description:ImportanceIdentifying gaps in inclusivity of Indigenous individuals is key to diversifying academic medical programs, increasing American Indian and Alaska Native representation, and improving disparate morbidity and mortality outcomes in American Indian and Alaska Native populations.ObjectiveTo examine representation of American Indian and Alaska Native individuals at different stages in the 2018-2019 academic medical training continuum and trends (2011-2020) of American Indian and Alaska Native representation in residency specialties.Design, setting, and participantsA cross-sectional, population-based analysis was conducted using self-reported race and ethnicity data on trainees from the Association of American Medical Colleges (2018), the Accreditation Council for Graduate Medical Education (2011-2018), and the US Census (2018). Data were analyzed between February 18, 2020, and March 4, 2021.ExposuresEnrolled trainees at specific stages of medical training.Main outcomes and measuresThe primary outcome was the odds of representation of American Indian and Alaska Native individuals at successive academic medical stages in 2018-2019 compared with White individuals. Secondary outcomes comprised specialty-specific proportions of American Indian and Alaska Native residents from 2011 to 2020 and medical specialty-specific proportions of American Indian and Alaska Native physicians in 2018. Fisher exact tests were performed to calculate the odds of American Indian and Alaska Native representation at successive stages of medical training. Simple linear regressions were performed to assess trends across residency specialties.ResultsThe study data contained a total of 238 974 607 White and American Indian and Alaska Native US citizens, 24 795 US medical school applicants, 11 242 US medical school acceptees, 10 822 US medical school matriculants, 10 917 US medical school graduates, 59 635 residents, 518 874 active physicians, and 113 168 US medical school faculty. American Indian and Alaska Native individuals had a 63% lower odds of applying to medical school (odds ratio [OR], 0.37; 95% CI, 0.31-0.45) and 48% lower odds of holding a full-time faculty position (OR, 0.52; 95% CI, 0.44-0.62) compared with their White counterparts, yet had 54% higher odds of working in a residency specialty deemed as a priority by the Indian Health Service (OR, 1.54; 95% CI, 1.09-2.16). Of the 33 physician specialties analyzed, family medicine (0.55%) and pain medicine (0.46%) had more than an average proportion (0.41%) of American Indian and Alaska Native physicians compared with their representation across all specialties.Conclusions and relevanceThis cross-sectional study noted 2 distinct stages in medical training with significantly lower representation of American Indian and Alaska Native compared with White individuals. An actionable framework to guide academic medical institutions on their Indigenous diversification and inclusivity efforts is proposed.

Dataset Information

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

Publications

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

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