Pharmacogenomics is the study of using your genome to predict your response to drugs. African ancestry populations, like African Americans, harbor more genetic diversity than any other world population, and hence they harbor genetic variants (e.g. single nucleotide polymorphisms or SNPs) that may only be found within this population. Many clinical phenotypes that have strong pharmacogenomic evidence (e.g. Clopidogrel response, an antiplatelet drug used after a patient has a stent placed in cardiac vessels) have never been investigated in African Americans; therefore, the unique SNPs that may contribute to the response of this drug are completely absent from the scientific literature.
Through the Discovery Project, we will identify predictable biomarkers (or SNPs) of cardiovascular drug response and disease susceptibility that can be investigated in translational outcome studies.
THERE ARE THREE AIMS:
AIM 1: Determine genetic predictors of drug response to thrombotic therapy using genome-wide association methodology.
AIM 2: Investigate the role of gene expression/splice variants and eQTLs on drug response phenotypes for elucidation of biological mechanisms and genetic regulation of these phenotypes.
AIM 3: Create a publically available and searchable database to house the results of the genomic and transcriptomic studies in African Americans
Thrombotic diseases disproportionately affect African Americans, and the role of genetics in the response to therapy in African Americans is still unknown. We will collect relevant clinical variables, adverse effects, and thrombotic disease information for cohorts starting therapy with the following drugs: Direct Xa oral anticoagulants (DOACs), warfarin, and Clopidogrel. In addition, we will also collect whole blood transcriptomes on all subjects to enable gene expression studies. These will be used to identify biological drivers of the measured clinical phenotypes or integrated with the genomic data from the same individual for the discovery of causative genetic variation (e.g. SNPs that associate with gene expression, alternative splicing, and drug response).
Building a Database
Currently, there is a lack of diversity in biomedical databases. This has stymied the ability of investigators to replicate study findings in African Americans, thus preventing these new discoveries from proceeding toward the clinic. The datasets (both genomics and transcriptomic) and resulting analysis from the Discovery Project will provide a much needed source of African American specific information for continued research in African American pharmacogenomics. Although existing databases contain searchable information on expression quantitative trait loci, these resources contain few to no information on African Americans. Our database will include the genotypes, phenotypes, and transcriptome in ACCOuNT, which will allow the scientific community to query SNP associations and expression quantitative trait loci (eQTLs) to gain insight into any genomic study in African Americans. Other investigators interested in African American genomics can examine their SNPs of interest for association with our clinical phenotypes or simply determine if their SNPs of interest are associated with gene expression/alternative splicing.
Minoli Perera, PharmD, PhD, Northwestern University
Arthur Harralson, PharmD, Shenandoah University
Teri Klein, PhD, Stanford University
Edith Nutescu, PharmD, University of Illinois at Chicago
Travis O’Brien, PhD, George Washington University
Matthew Tuck, MD, Washington DC VA Medical Center
Please visit the Resources page for more information on prior research related to the discovery of genetic variations and race.