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Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans
Author(s) -
Hernandez W.,
Gamazon E. R.,
AquinoMichaels K.,
Smithberger E.,
O'Brien T. J.,
Harralson A. F.,
Tuck M.,
Barbour A.,
Cavallari L. H.,
Perera M. A.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13639
Subject(s) - warfarin , genetic variation , gene , variation (astronomy) , genetics , genetic variants , gene expression , biology , computational biology , medicine , genotype , atrial fibrillation , physics , astrophysics
Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population‐specific variation in gene regulation.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 VKORC 1 and CYP 2C9 polymorphisms explain only a small proportion of inter‐individual variability in African Americans ( AA s). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AA s. Patients/Methods We identified a total of 56 expression quantitative trait loci ( eQTL s) for CYP 2C9 , VKORC 1 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 VKORC 1 (log 10 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 VKORC 1 ‐1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP 2C9 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 AA s and European Americans, which may explain the increased dose requirement found in AA s. Conclusion Our approach of interrogating eQTL s identified in liver has revealed a novel predictor of warfarin dose response in AA s. 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.