title: A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans.
abstract: Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.
authors.affiliation: Department of Medicine, Washington University in St Louis, St Louis, Missouri, USA.
authors.forename: D
authors.initials: D
authors.lastname: Voora
authors.forename: D C
authors.initials: DC
authors.lastname: Koboldt
authors.forename: C R
authors.initials: CR
authors.lastname: King
authors.forename: P A
authors.initials: PA
authors.lastname: Lenzini
authors.forename: C S
authors.initials: CS
authors.lastname: Eby
authors.forename: R
authors.initials: R
authors.lastname: Porche-Sorbet
authors.forename: E
authors.initials: E
authors.lastname: Deych
authors.forename: M
authors.initials: M
authors.lastname: Crankshaw
authors.forename: P E
authors.initials: PE
authors.lastname: Milligan
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
authors.forename: S R
authors.initials: SR
authors.lastname: Patel
authors.forename: L H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: P M
authors.initials: PM
authors.lastname: Ridker
authors.forename: G R
authors.initials: GR
authors.lastname: Grice
authors.forename: R D
authors.initials: RD
authors.lastname: Miller
authors.forename: B F
authors.initials: BF
authors.lastname: Gage
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics
chemical_list: D000925:Anticoagulants; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases