Ancestry and sex-related pharmacogenomic and metabolomic signatures of oral anticoagulant response - Oral anticoagulants (OACs), including warfarin and direct oral anticoagulants (DOACs), form the cornerstone of therapy for thromboembolic conditions. However, individual variability in OAC response can result in lack of efficacy (thromboembolism) or safety (hemorrhage), with OAC-related hemorrhage a serious adverse effect. Ancestry and sex influence OAC response and variable drug levels, therapeutic target levels, and clinical OAC responses have been observed. Differences in pharmacogenomic variant frequencies, gene expression, and metabolite profiles by ancestry and sex may explain variable drug response. However, pharmacogenomic evaluations of DOAC response have been limited in diversity, evaluated candidate genes, and lacked evaluation of sex-related predictors. Furthermore, metabolomics signatures of variable OAC response have not been evaluated. This is a major barrier to establishing therapeutic drug and biomarker levels and personalizing OAC therapy. The NIH recognizes the importance of identifying factors that affect treatment response among diverse patients and the use of pharmacogenomics and metabolomics to identify and develop new therapeutic targets/ biomarkers. With the support of this K23 award, Brittney Davis, PharmD will identify and evaluate ancestry and sex-related pharmacogenomic and metabolomic signatures of variable OAC response, including pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes (hemorrhage). This will be achieved through integrated research and training aims that build on her prior clinical and research background. Specifically, she will evaluate pharmacogenomic predictors of DOAC PK (drug levels) and PD (anti-Xa levels), and integrate pathway and functional effects to characterize drug response pathways (Aim 1). To evaluate clinical outcomes, she will identify pharmacogenomic predictors of OAC-related hemorrhage employing a DOAC-specific approach and a combined drug class approach (warfarin + DOAC), and replicate findings in an independent cohort identified using electronic medical record (EMR)-based phenotyping (Aim 2). Finally, she will conduct metabolomics analysis and characterize signatures of anti-Xa and OAC-related hemorrhage to determine if metabolite profiles can be serve as OAC response biomarkers. This project provides a highly significant opportunity to employ strategies to identify and target DOAC and anti-Xa threshold concentrations, which could help maximize efficacy and safety, elucidate biologic pathways and metabolomic signatures of variable response, and lay the foundation for personalized strategies. To achieve her research and career goals, Dr. Davis has constructed a multidisciplinary mentoring team with extensive expertise in areas relevant to her career development, including 1) bioinformatics/statistical genetics 2) metabolomics and pathway analysis 3) electronic medical record (EMR)-based phenotyping and 4) clinical research. This mentored training experience at the University of Alabama at Birmingham will lay the foundation for an independent career focused on integrative pharmacogenomics and metabolomics approaches to personalize OAC therapy.
