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

D. Voora, D. C. Koboldt, C. R. King, P. A. Lenzini, C. S. Eby, R. Porche-Sorbet, E. Deych, M. Crankshaw, P. E. Milligan, H. L. McLeod, S. R. Patel, L. H. Cavallari, P. M. Ridker, G. R. Grice, R. D. Miller, B. F. Gage

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish
Pages (from-to)445-451
Number of pages7
JournalClinical pharmacology and therapeutics
Volume87
Issue number4
DOIs
StatePublished - Apr 2010

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