Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations

Abstract

The oral vitamin K antagonist warfarin (Coumadin®) is used to prevent stroke in patients with atrial fibrillation and for secondary prevention of venous thromboembolism. Despite newer treatment options such as the direct oral anticoagulants, warfarin remains a mainstay in anticoagulation therapy. Warfarin therapy requires intensive monitoring and dose titration due to its narrow therapeutic index and wide inter-individual response, due in part to genetic variation, as well as clinical, demographic, and environmental factors. While variation in VKORC1, CYP2C9, CYP4F2 and GGCX genes have been associated with the warfarin dose required to achieve a therapeutic anticoagulation response, these findings are based largely on variant alleles and their frequencies found in populations largely of European descent, and may not be generalizable to other, less studied populations such as Alaska Native and American Indian (AN/AI) people. It is important to characterize the unique genetic variation that exists in the AN/AI population because there are clinical implications of having uncharacterized genetic variation (eg, phenotype misclassification), particularly with drug metabolizing enzymes and drug target proteins. The projects described in this dissertation proposal inform on personalized warfarin therapy for AN/AI patients living in remote communities of Alaska and investigate the missing heritability in warfarin dose variance. Chapter 2 and 3 describe the in vitro and in vivo characterization of novel variation in CYP2C9 found in the indigenous population of Alaska. In Chapter 4, the impact of CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX gene variation on stable warfarin dose was determined in an AN/AI population living in Southcentral Alaska. Chapter 5 seeks to better understand the variability in warfarin dose through a pathway-based analysis identifying potential regulators of VKORC1 that influence VKOR expression, and therefore warfarin dose requirement. This dissertation research has improved our understanding of the clinical relevance of VKORC1 as a determinant of therapeutic warfarin dose requirement in AN/AI people as well as the pharmacokinetic impact of novel CYP2C9 variation on warfarin metabolism and pharmacological response, in addition to other narrow therapeutic index CYP2C9 substrates. Overall, this data can be used to implement population-specific genetic variation in clinical decisions associated with personalized or precision medicine, and to assess whether pharmacogenetic testing provides unique advantages in rural AN/AI communities.