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

作者：Voora D; Koboldt D C; King C R; Lenzini P A; Eby C S; Porche Sorbet R; Deych E; Crankshaw M; Milligan P E; McLeod H L; Patel S R; Cavallari L H; Ridker P M; Grice G R; Miller R D; Gage B F^*

来源：Clinical Pharmacology & Therapeutics, 2010, 87(4): 445-451.

DOI：10.1038/clpt.2009.291

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.

• 出版日期2010-4