Pharmacogenetics of Select Genes in the Opiate Metabolism and Response Pathways




Wendt, Frank R.


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Pharmacogenetics and pharmacogenomics aim to elucidate the underlying genetic variation contributing to adverse drug reactions, differential enzyme activity, and resulting appropriate drug dosage on the individual and population levels. Studies with this goal in mind typically rely on targeted genotyping of select single nucleotide polymorphisms (SNPs) and/or insertion/deletion (INDEL) polymorphisms within a gene that have demonstrated significant association with the rate of drug absorption, distribution, excretion, and/or metabolism. This approach may enable association and characterization of clinically relevant polymorphisms with a phenotype of interest and may provide guidance regarding appropriate prescription medication practices for medical professionals. Additionally, these data, namely those of the cytochrome p450, family 2, subfamily D, polypeptide 6 gene (CYP2D6), have contributed to identifying cause and/or manner of death in some death investigations which initially were negative medico-legal autopsies. Though invaluable to medical genetics, the chemistry of targeted genotyping approaches, including genome-wide association studies and SNP-targeted massively parallel sequencing, inherently lack the capability to discover novel or rare polymorphisms that may be enriched in pharmacogenetically-valuable cohorts (i.e., individuals who have experienced idiosyncratic responses to codeine/morphine). Relatively recently, the pharmacogenetics community has utilized comprehensive (i.e., full-gene) and/or combinatorial (i.e., multi-gene) genetic studies using multiple genes whose protein products are involved in a drug metabolism/response pathway. The multi-gene approach is demonstrably more successful in predicting phenotypic expressions and more efficacious for patient outcomes compared to as single-gene approach. While mainly elucidating multigenic profiles of psychiatric drugs and disorders, to date, it is reasonable to consider that more efficacious patient outcomes can be achieved using the pathways responsible for other pathologies or drug metabolism and response pathways. The goal of this dissertation was to develop a comprehensive genetic profiling system using the full gene region of five genes that have demonstrated associations between specific SNPs and opiate metabolism/response. The in silico phases of this dissertation aimed to characterize the genes encoding CYP2D6, uridine diphosphate glucuronosyltransferase family 1 polypeptide B7 (UGT2B7), adenosine triphosphate (ATP) binding cassette subfamily B number 1 (ABCB1; p-glycoprotein; multidrug resistance protein 1), opioid receptor mu 1 (OPRM1; MOR1), and catechol-O-methyltransferase (COMT) on the individual SNP and full-gene haplotype levels. Subsequent empirical evaluation of these genes was performed on a cohort of deceased tramadol-exposed Finns using targeted genotyping and exome-wide analyses. This dissertation research has 1) described previously uncharacterized individual SNPs that are associated with the metabolism of tramadol to its primary metabolite, O-desmethyltramadol; 2) evaluated the utility of full-gene information for predicting metabolizer phenotype; 3) produced a massively parallel sequencing panel to genotype opiate-metabolism genes in a more comprehensive and combinatorial manner than previously attempted; 4) demonstrated the increased predictive capabilities of a multigenic opiate metabolizer phenotyping system; and 5) identified additional genetic targets that may have predictive phenotypic value.