VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People. Issue 3 (1st March 2019) - Henderson, Lindsay M.
Abstract : 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 ( VKORC1 ), CYP4F2, CYP4F11, 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. VKORC1 genotype explained 34% of dose variability, with VKORC1 −1639G>A and 1173C>T associated with a 1.7 mg/day ( P = 1.4e‐05) dose reduction. Additionally, CYP2C9 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 VKORC1 allele frequencies among AN/AI people.