title: Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.
abstract: 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.
  
  
  
  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 (log10Bayes 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.
authors.affiliation: Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Hernandez
authors.affiliation: Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.|Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Aquino-Michaels
authors.affiliation: Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Smithberger
authors.affiliation: Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, George Washington University, Washington, DC, USA.|Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Harralson
authors.affiliation: Veterans Affairs Medical Center, Washington, DC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tuck
authors.affiliation: Department of Medicine, George Washington University, Washington, DC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Barbour
authors.affiliation: Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Cavallari
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Perera
mesh_terms: D000328:Adult; D001741:Black or African American; D000368:Aged; D000465:Algorithms; D002135:Calcium-Binding Proteins / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D057285:Precision Medicine; D040641:Quantitative Trait Loci; D013923:Thromboembolism / Q000188:drug therapy / Q000208:ethnology* / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: African American; pharmacogenetics; quantitative trait loci; thromboembolism; warfarin