title: The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans.
abstract: It is well recognized that the genetic variants VKORC1-1639, CYP2C9*2, and CYP2C9*3 contribute to warfarin dose response. This has led to warfarin dosing algorithms that include these polymorphisms and explains between 47% and 56% of variability in dose in Caucasians. However, these polymorphisms explain significantly less of the variance in dose among African Americans. In order to identify novel variations that affect warfarin dose in African Americans, we used a targeted resequencing strategy that examined evolutionarily conserved sequences and regions of putative transcriptional binding. Through ethnicity-specific warfarin dose model building in 330 African Americans, we identified two novel genetic associations with higher warfarin dose, namely, VKORC1-8191 (rs61162043, P = 0.0041) and 18786 in CYP2C9 (rs7089580, P = 0.035). These novel finds are independent of the previous associations with these genes. Our regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin dose in African-American subjects, significantly more than any model thus far.
authors.affiliation: Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, Illinois, USA. mperera@bsd.uchicago.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Perera
authors.forename: E
authors.initials: E
authors.lastname: Gamazon
authors.forename: L H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: S R
authors.initials: SR
authors.lastname: Patel
authors.forename: S
authors.initials: S
authors.lastname: Poindexter
authors.forename: R A
authors.initials: RA
authors.lastname: Kittles
authors.forename: D
authors.initials: D
authors.lastname: Nicolae
authors.forename: N J
authors.initials: NJ
authors.lastname: Cox
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases