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Alaska Native and American Indian ( AN / AI ) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (  CYP  ) 2C9 , vitamin K epoxide oxidase reductase complex subunit 1 (  VKORC 1 ),   CYP 4F2 ,   CYP 4F11 , and gamma‐glutamyl carboxylase (  GGCX  ) variants in  AN / AI  people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype–phenotype relationships were assessed by multivariate regression analysis, adjusted for self‐reported heritage, age, gender, and concurrent statin use.   VKORC 1  genotype explained 34% of dose variability, with   VKORC 1 −1639G>A  and  1173C>T  associated with a 1.7 mg/day ( P  = 1.4e‐05) dose reduction. Additionally,   CYP 2C9 N218I  was suggestively significant ( P  = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self‐reported heritage was significantly associated with dose, largely driven by differences in the diagnostic   VKORC 1  allele frequencies among  AN / AI  people.

VKORC 1 and Novel CYP 2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People