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Variation in Genes Controlling Warfarin Disposition and Response in American Indian and Alaska Native People: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX

Fohner, A.E., Robinson, R., Yracheta, J. et al.

Objectives
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 inter-individual 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 (SCF) in Anchorage, AK 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 SNPs 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 US, a finding consistent with clinical experience in Alaska.

Citation

Fohner, A.E., Robinson, R., Yracheta, J. et al. "Variation in Genes Controlling Warfarin Disposition and Response in American Indian and Alaska Native People: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX" Pharmacogenetic Genomics (2015): 343–53