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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Voora, D; Koboldt, DC; King, CR; Lenzini, PA; Eby, CS; Porche-Sorbet, R; Deych, E; Crankshaw, M; Milligan, PE; McLeod, HL; Patel, SR; Cavallari, LH; Ridker, PM; Grice, GR; Miller, RD; Gage, BF

Published Date

  • April 2010

Published In

Volume / Issue

  • 87 / 4

Start / End Page

  • 445 - 451

PubMed ID

  • 20200517

Pubmed Central ID

  • PMC2928561

Electronic International Standard Serial Number (EISSN)

  • 1532-6535

Digital Object Identifier (DOI)

  • 10.1038/clpt.2009.291


  • eng

Conference Location

  • United States