VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People. Issue 3 (1st March 2019)

• Record Type: Journal Article
• 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.
• Is Part Of: Clinical and translational science. Volume 12:Issue 3(2019)
• Page Start: 312
• Page End: 320
• Publication Date: 2019-03-01
• Subjects: Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; 616.027
• DOI: 10.1111/cts.12611
• Languages: English
• ISSNs: 1752-8054

Abstract

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.