title: Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Fohner
authors.affiliation: Southcentral Foundation, Anchorage, AK.
authors.forename: Renee
authors.initials: R
authors.lastname: Robinson
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Yracheta
authors.affiliation: Southcentral Foundation, Anchorage, AK.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Dillard
authors.affiliation: Southcentral Foundation, Anchorage, AK.
authors.forename: Brian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Southcentral Foundation, Anchorage, AK.
authors.forename: Burhan
authors.initials: B
authors.lastname: Khan
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, AK.
authors.forename: Scarlett
authors.initials: S
authors.lastname: Hopkins
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, AK.
authors.forename: Bert
authors.initials: B
authors.lastname: Boyer
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, AK.
authors.forename: Jynene
authors.initials: J
authors.lastname: Black
authors.affiliation: School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Howard
authors.initials: H
authors.lastname: Wiener
authors.affiliation: School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle WA.
authors.forename: Adam
authors.initials: A
authors.lastname: Gordon
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle WA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Tsai
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington.
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.affiliation: Department of Biostatistics, University of Washington.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Thornton
authors.affiliation: Department of Medicinal Chemistry, University of Washington.
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
mesh_terms: D000413:Alaska; D000072957:Alaska Natives / Q000235:genetics*; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019735:Carbon-Carbon Ligases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014812:Vitamin K / Q000037:antagonists & inhibitors; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C492722:CYP4F11 protein, human; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase