title: Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Public Health Genetics, School of Public Health, University of Washington, Seattle, Washington, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Fohner
authors.forename: LeeAnna I
authors.initials: LI
authors.lastname: Muzquiz
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Austin
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Adam
authors.initials: A
authors.lastname: Gordon
authors.forename: Timothy
authors.initials: T
authors.lastname: Thornton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pershouse
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Putnam
authors.forename: Kevin
authors.initials: K
authors.lastname: Howlett
authors.forename: Patrick
authors.initials: P
authors.lastname: Beatty
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Erica L
authors.initials: EL
authors.lastname: Woodahl
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D056915:DNA Copy Number Variations; D014644:Genetic Variation; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008875:Middle Aged; D015205:Northwestern United States; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human