Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Healthcare Genetics

Committee Chair/Advisor

Dr. Sara M. Sarasua, Committee Chair

Committee Member

Dr. Luigi Boccuto, Committee Co-Chair

Committee Member

Dr. Christopher Farrell

Committee Member

Dr. Deborah Kunkel


Pharmacogenomics, the study of the genetic contribution to inter-individual differences in drug response, has great potential for realizing the goals of precision medicine: the right drug, for the right patient, at the right time. However, application in the clinical setting, through the use of pharmacogenetic testing, still has not gained widespread acceptance. This work describes multiple aspects of pharmacogenomics, which drive current research in this field.

Chapter I is an introduction to pharmacogenomics. Regulatory agencies and professional organizations across the globe provide information about gene-drug interactions that could lead to adverse drug reactions, and/or therapeutic failure. Risks for poor health outcomes are related to genetic variants of enzymes, transport proteins, or target proteins. The nomenclature used to represent variants, and the methods used to translate these variants into clinical phenotypes are described. Barriers to the implementation of pharmacogenetic testing are discussed.

Chapter II is a literature review of the evidence for the clinical utility of pharmacogenetic testing in patients with polypharmacy. The goal was to assess the real-world impact of pharmacogenetic testing, keeping in mind that many patients have comorbidities. We found very few articles that directly addressed this issue. In general, pharmacogenetic testing lead to improved health outcomes, but non-genetic factors that impact drug response can also have implications for the implementation of genetics-guided therapy.

Chapter III reviews the role of genetics and environmental factors in gut microbiota-human host interactions. This topic illustrates that gene expression can be influenced by extrinsic factors, a concern for the accurate implementation of pharmacogenetic testing. Bacteria in the human gut express genes related xenobiotic metabolism and can produce metabolites that influence gene expression through epigenetic regulation. The gut microbiota may also contribute to the development of gastrointestinal disorders through changes in transcriptional regulation. We reviewed microbial enzymes capable of drug biotransformation as well. The impact of the gut microbiome on therapeutic interventions has been recognized as an area worth further investigation, a field of study known as pharmacomicrobiomics.

Chapter IV is an investigation of CYP2D6 gene expression in the human liver, the main site of drug metabolism. Several CYP2D6 genetic polymorphisms are known to alter enzyme function, affecting the therapeutic efficacy of medications metabolized by CYP2D6. We proposed that variability in CYP2D6 gene expression in the liver could also offer an explanation for variability in drug response in patients. After an analysis of genetic sequencing and RNA-Seq data from normal and tumor tissue, a wide range of gene expression was observed in individuals with the same CYP2D6 genotype. Our analyses also revealed that mRNA levels of transcription factors HNF4A and NR0B2 are predictors of CYP2D6 expression. The data suggest that inter-individual variation in CYP2D6 gene expression may be a barrier to the implementation of pharmacogenetic testing results.

Chapter V is a review of multiple considerations in patient care discussed in this work, that should drive research in pharmacogenomics in order to enhance the clinical utility of genetics-guided drug dosing. Greater availability of pharmacogenomics education and clinical decision support tools would make research findings more accessible to clinicians, and further the goals of precision medicine.

Available for download on Saturday, August 31, 2024