title: A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose.
abstract: We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeuchi
authors.forename: Ralph
authors.initials: R
authors.lastname: McGinnis
authors.forename: Stephane
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Chris
authors.initials: C
authors.lastname: Barnes
authors.forename: Niclas
authors.initials: N
authors.lastname: Eriksson
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Pamela
authors.initials: P
authors.lastname: Whittaker
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Ranganath
authors.forename: Vasudev
authors.initials: V
authors.lastname: Kumanduri
authors.forename: William
authors.initials: W
authors.lastname: McLaren
authors.forename: Lennart
authors.initials: L
authors.lastname: Holm
authors.forename: Jonatan
authors.initials: J
authors.lastname: Lindh
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D055106:Genome-Wide Association Study; D006801:Humans; D008660:Metabolism / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases