Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX

Alison E. Fohner, Renee Robinson, Joseph Yracheta, Denise A. Dillard, Brian Schilling, Burhan Khan, Scarlett Hopkins, Bert B. Boyer, Jynene Black, Howard Wiener, Hemant K. Tiwari, Adam Gordon, Deborah Nickerson, Jesse M. Tsai, Federico M. Farin, Timothy A. Thornton, Allan E. Rettie, Kenneth E. Thummel

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)343-353
Number of pages11
JournalPharmacogenetics and Genomics
Volume25
Issue number7
DOIs
StatePublished - Jun 19 2015

Keywords

  • Coumadin
  • cytochrome P450
  • indigenous populations
  • individualized therapy
  • personalized medicine
  • underserved populations

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX'. Together they form a unique fingerprint.

  • Cite this

    Fohner, A. E., Robinson, R., Yracheta, J., Dillard, D. A., Schilling, B., Khan, B., Hopkins, S., Boyer, B. B., Black, J., Wiener, H., Tiwari, H. K., Gordon, A., Nickerson, D., Tsai, J. M., Farin, F. M., Thornton, T. A., Rettie, A. E., & Thummel, K. E. (2015). Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX. Pharmacogenetics and Genomics, 25(7), 343-353. https://doi.org/10.1097/FPC.0000000000000143