title: Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups.
abstract: Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.
authors.affiliation: University of Alabama at Birmingham, USA.
authors.forename: Nita A
authors.initials: NA
authors.lastname: Limdi
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
authors.forename: Larisa
authors.initials: L
authors.lastname: Cavallari
authors.forename: Niclas
authors.initials: N
authors.lastname: Eriksson
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Ming-Ta M
authors.initials: MT
authors.lastname: Lee
authors.forename: Chien-Hsiun
authors.initials: CH
authors.lastname: Chen
authors.forename: Alison
authors.initials: A
authors.lastname: Motsinger-Reif
authors.forename: Hersh
authors.initials: H
authors.lastname: Sagreiya
authors.forename: Nianjun
authors.initials: N
authors.lastname: Liu
authors.forename: Alan H B
authors.initials: AH
authors.lastname: Wu
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gage
authors.forename: Andrea
authors.initials: A
authors.lastname: Jorgensen
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Guilherme
authors.initials: G
authors.lastname: Suarez-Kurtz
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kimmel
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wagner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics*; D012307:Risk Factors; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases