Pharmacogenetics in American Indian populations: Analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the confederated salish and kootenai tribes

Alison Fohner, Leeanna I. Muzquiz, Melissa A. Austin, Andrea Gaedigk, Adam Gordon, Timothy Thornton, Mark J. Rieder, Mark A. Pershouse, Elizabeth A. Putnam, Kevin Howlett, Patrick Beatty, Kenneth E. Thummel, Erica L. Woodahl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

OBJECTIVES: Cytochrome P450 enzymes play a dominant role in drug elimination and variation in these genes is a major source of interindividual differences in drug response. Little is known, however, about pharmacogenetic variation in American Indian and Alaska Native (AI/AN) populations. We have developed a partnership with the Confederated Salish and Kootenai Tribes (CSKT) in northwestern Montana to address this knowledge gap. METHODS: We resequenced CYP2D6 in 187 CSKT individuals and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT individuals. RESULTS: We identified 67 variants in CYP2D6, 15 in CYP3A4, 10 in CYP3A5, and 41 in CYP2C9. The most common CYP2D6 alleles were CYP2D6*4 and *41 (20.86 and 11.23%, respectively). CYP2D6*3, *5, *6, *9, *10, *17, *28, *33, *35, *49, *1xN, *2xN, and *4xN frequencies were less than 2%. CYP3A5*3, CYP3A4*1G, and *1B were detected with frequencies of 92.47, 26.81, and 2.20%, respectively. Allelic variation in CYP2C9 was low: CYP2C9*2 (5.17%) and *3 (2.69%). In general, allele frequencies in CYP2D6, CYP2C9, and CYP3A5 were similar to those observed in European Americans. There was, however, a marked divergence in CYP3A4 for the CYP3A4*1G allele. We also observed low levels of linkage between CYP3A4*1G and CYP3A5*1 in the CSKT. The combination of nonfunctional CYP3A5*3 and putative reduced function CYP3A4*1G alleles may predict diminished clearance of CYP3A substrates. CONCLUSION: These results highlight the importance of carrying out pharmacogenomic research in AI/AN populations and show that extrapolation from other populations is not appropriate. This information could help optimize drug therapy for the CSKT population.

Original languageEnglish (US)
Pages (from-to)403-414
Number of pages12
JournalPharmacogenetics and genomics
Volume23
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Alaska Native
  • American Indian
  • CYP2C9
  • CYP2D6
  • CYP3A4
  • CYP3A5
  • cytochrome P450
  • indigenous populations
  • pharmacogenetics
  • pharmacogenomics

ASJC Scopus subject areas

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

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