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

• Main Authors: Lindsay M. Henderson (Author), Renee F. Robinson (Author), Lily Ray (Author), Burhan A. Khan (Author), Tianran Li (Author), Denise A. Dillard (Author), Brian D. Schilling (Author), Mike Mosley (Author), Patricia L. Janssen (Author), Alison E. Fohner (Author), Allan E. Rettie (Author), Kenneth E. Thummel (Author), Timothy A. Thornton (Author), David L. Veenstra (Author)
• Format: Book
• Published: Wiley, 2019-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

1752-8062
1752-8054
10.1111/cts.12611