TY - JOUR
T1 - Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people
T2 - CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX
AU - Fohner, Alison E.
AU - Robinson, Renee
AU - Yracheta, Joseph
AU - Dillard, Denise A.
AU - Schilling, Brian
AU - Khan, Burhan
AU - Hopkins, Scarlett
AU - Boyer, Bert B.
AU - Black, Jynene
AU - Wiener, Howard
AU - Tiwari, Hemant K.
AU - Gordon, Adam
AU - Nickerson, Deborah
AU - Tsai, Jesse M.
AU - Farin, Federico M.
AU - Thornton, Timothy A.
AU - Rettie, Allan E.
AU - Thummel, Kenneth E.
N1 - Publisher Copyright:
© 2015 Wolters Kluwer Health, Inc.
PY - 2015/6/19
Y1 - 2015/6/19
N2 - 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.
AB - 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.
KW - Coumadin
KW - cytochrome P450
KW - indigenous populations
KW - individualized therapy
KW - personalized medicine
KW - underserved populations
UR - http://www.scopus.com/inward/record.url?scp=84931058500&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84931058500&partnerID=8YFLogxK
U2 - 10.1097/FPC.0000000000000143
DO - 10.1097/FPC.0000000000000143
M3 - Article
C2 - 25946405
AN - SCOPUS:84931058500
SN - 1744-6872
VL - 25
SP - 343
EP - 353
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
IS - 7
ER -