Summary
Background
Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose–requirement relationship, safe and effective use is challenging. Pharmacogenomics‐guided warfarin dosing algorithms that include the well‐established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter‐individual variability in African Americans (AAs).
Objectives
We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs.
Patients/Methods
We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts.
Results
We found that rs4889606, a strong cis‐eQTL for VKORC1 (log10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 −1.7; n = 141) after conditioning on relevant covariates and the VKORC1 ‐1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter‐patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs.
Conclusion
Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population‐specific research.