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Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

ABSTRACT: Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4-hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population.

SUBMITTER: Khan BA

PROVIDER: S-EPMC5944577 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

Khan Burhan A BA Robinson Renee R Fohner Alison E AE Muzquiz LeeAnna I LI Schilling Brian D BD Beans Julie A JA Olnes Matthew J MJ Trawicki Laura L Frydenlund Holly H Laukes Cindi C Beatty Patrick P Phillips Brian B Nickerson Deborah D Howlett Kevin K Dillard Denise A DA Thornton Timothy A TA Thummel Kenneth E KE Woodahl Erica L EL

Clinical and translational science 20180213 3

Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations ...[more]

PMID: 29436156

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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

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

Publications

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

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