Discovery of genomic copy number variants and expression quantitative trait loci that affect warfarin dose response in African Americans - Resubmission 01

University Of Chicago, Chicago IL

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Abstract

? DESCRIPTION (provided by applicant): The primary goal of this project is to develop a polygenic prediction model to more comprehensively account for the genetic variation observed in warfarin dose requirement in African Americans (AAs) by leveraging information from regulatory variants mapped in the liver, the tissue most relevant to warfarin metabolism. Warfarin is the most commonly prescribed anticoagulant for prevention or treatment of thromboembolic diseases. However, due to its narrow therapeutic index and wide variability in dose requirement among individuals, warfarin ranks among the top ten drug-related causes of serious adverse effects including death. Few single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 genes have been well established to contribute to warfarin dose response and have been incorporated into warfarin dosing algorithms. But since these polymorphisms were identified largely from Caucasian population studies, are found in lower frequency in African Americans, and have been predominantly associated with enhanced warfarin sensitivity they explain significantly less of the variance in dose among African Americans compared to Caucasians (<20% versus >55%) - indicating that the population-specific genetic basis for warfarin dose response in AAs is largely unexplained. Recently, our laboratory has identified a significant enrichment expression quantitative trait loci (eQTLs) mapped in human liver tissue among the top associations with warfarin dose response that were not detected by traditional genome-wide association studies (GWAS). We will also examine copy number variants (CNVs) which are structural variants ranging from 1kb to megabases and can encompass genes leading to dosage imbalances. The extent to which eQTLs and CNVs can serve as predictors of warfarin dose response has not been studied. This study will explore novel predictive models of warfarin dose response that incorporates multiple liver eQTLs and/or CNVs information to improved dose response prediction in the African American patient population. The specific aims of this proposal are (1) to identify multiple genetic variants that contribute to warfarin dose response in African Americans and build a model to predict dose and (2) to identify CNVs that contribute to warfarin dose requirement in African Americans. The proposed project will result in a novel polygenic prediction model that will aid in the treatment of cardiovascular diseases. Ultimately, we hope to decrease incidence of adverse effects, including death, attributed to under-dosing or over-dosing African American patients on warfarin.