Open AccessVKORC 1 and Novel CYP 2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People
Author(s) -
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.
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12611
Subject(s) - vitamin k epoxide reductase , cyp2c9 , warfarin , vkorc1 , genotype , medicine , genotyping , biology , pharmacology , cytochrome p450 , genetics , atrial fibrillation , metabolism , gene
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.