Title: VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People.

Authors: Henderson, Lindsay M; Robinson, Renee F; Ray, Lily; Khan, Burhan A; Li, Tianran; Dillard, Denise A; Schilling, Brian D; Mosley, Mike; Janssen, Patricia L; Fohner, Alison E; Rettie, Allan E; Thummel, Kenneth E; Thornton, Timothy A; Veenstra, David L

Published In Clin Transl Sci, (2019 May)

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.

PubMed ID: 30821933

MeSH Terms: Alaska Natives/genetics*; Cytochrome P-450 CYP2C9/genetics*; Dose-Response Relationship, Drug; Female; Humans; Indians, North American/genetics*; Linear Models; Male; Middle Aged; Mutation/genetics*; Self Report; Vitamin K Epoxide Reductases/genetics*; Warfarin/therapeutic use*