A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans

Clin Pharmacol Ther. 2010 Apr;87(4):445-51. doi: 10.1038/clpt.2009.291. Epub 2010 Mar 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Validation Study

MeSH terms

  • Adult
  • African Americans / genetics*
  • Aged
  • Alleles
  • Anticoagulants / administration & dosage*
  • Calcium-Binding Proteins / genetics*
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • European Continental Ancestry Group / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / metabolism*
  • Polymorphism, Single Nucleotide
  • Vitamin K Epoxide Reductases
  • Warfarin / administration & dosage*

Substances

  • Anticoagulants
  • CALU protein, human
  • Calcium-Binding Proteins
  • Warfarin
  • Mixed Function Oxygenases
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases