The effect of NAD(P)H dehydrogenase, quinone 1 genotype on warfarin dose requirements in Hispanic and African Americans

Purpose: Warfarin is the most widely used oral anticoagulant, but its usability is limited by a narrow therapeutic index and nearly a 20-fold variation in dose requirements. The objective of this study was to determine the additional contribution of NAD(P)H dehydrogenase, quinone 1 (NQO1) genotype to warfarin dose requirements across two racial groups after accounting for VKORC1, CYP2C9, and CYP4F2 genotypes. 

Methods: A total of 313 patients were enrolled, including 260 African Americans and 53 Hispanic Americans.  After obtaining written informed consent and a genetic sample, the following factors were assessed: demographics; clinical data; NQO1 Pro187Ser (*1/*2); CYP2C9 Arg144Cys (*2), Ile359Leu (*3), Asp360Glu (*5), and Arg150His (*8); CYP4F2 Val433Met; and VKORC1 -1639G>A genotypes.

Results: The NQ01*2 allele frequency was higher in Hispanics compared to African Americans (0.27 vs. 0.18, p=0.05). There was no association between NQO1*2 (genotype and warfarin dose requirements in either race by bivariate analysis. However, after adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical (age, body size, history of hypertension or atrial fibrillation) factors, possession of the NQ01*2 allele was associated with a 35% increase in warfarin maintenance dose (p=0.004) in Hispanics.  In this population, the inclusion of NQO1*2 genotype improved the dose variability explained by the model from 0.62 to 0.68 (p=0.004), a 10% improvement. In contrast, we found no association between NQ01*2 genotype and therapeutic warfarin dose in African Americans after adjusting for known genetic and clinical predictors.

Conclusion: In our cohort of inner city U.S Hispanics, NQO1 genotype was significantly associated with warfarin dose requirements after holding clinical and genetic predictors constant.  If our findings are confirmed, they would suggest that inclusion of NQO1*2 genotype in warfarin dosing algorithms may improve the predictive ability of such algorithms in Hispanics.