A Polymorphism in the VKORC1 Regulator Calumenin Predicts Higher Warfarin Dose Requirements in African Americans

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. Clinical Pharmacology & Therapeutics (2010) 87 4, 445–451. doi: 10.1038/clpt.2009.291