Understanding the genetic basis of disease and drug response has the potential to improve therapy and enable early intervention or prevention. However, the main genetic factors remain only partially understood, even while the number of candidate genes is rapidly growing, as a result of genome-wide association studies. Polymorphisms that alter protein sequence are readily detectable, but growing evidence indicates that regulatory polymorphisms are more prevalent, affecting mRNA expression, processing, and translation. Yet, regulatory variants are difficult to detect, and moreover, their functions depend on tissue context and environment, so that a majority remains hidden. The central goal of this proposal is a comprehensive discovery of regulatory polymorphisms in ~200 pharmacotherapeutic candidate genes, followed by molecular studies to understand the underlying mechanisms, and clinical evaluation in drug therapy - the first such systematic study in pharmacogenomics. We have developed a comprehensive approach to the discovery of regulatory polymorphisms, measuring allelic mRNA expression, processing, and translation in relevant human target tissues. This approach has already revealed unexpected and frequent regulatory variants in genes encoding drug metabolizing enzymes and receptors, gaining a powerful link between genotype of proven function and clinical outcomes (examples: DRD2, TPH2, ACE, VKORC1, CETP, and CYP3A4). These results support a critical role for regulatory polymorphisms in drug response. The main focus in this proposal is on drug metabolism genes and impact on pharmacokinetics-pharmacodynamics. In addition, building on other ongoing studies, the project includes genes encoding drug receptors/targets, with focus on CNS disorders (schizophrenia) and cardiovascular diseases (myocardial infarction, lipid metabolism), to be tested in association studies led by experienced clinical scientists. Driven by the motto 'from clinic to laboratory', new genetic studies have been initiated on estrogen and glucocorticoid receptors, the latter to be tested in glucocorticoid-resistant nephrotic syndrome in children. The long-term goal is to develop and validate genetic biomarker panels for optimizing personalized drug therapy.

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Advances in genomic sciences have raised expectations that drug therapy can be tailored to the individual patient. However, a large portion of genetic variability remains to be discovered. The 'Expression Genetics in Drug Therapy'program aims to fill an important gap, through a systematic study of gene regulation of drug metabolizing enzymes and receptors. We expect to develop genetic biomarkers for optimizing drug therapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-GGG-M (52))
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Long, Rochelle M
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Ohio State University
Schools of Medicine
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Papp, Audrey C; Azad, Abul K; Pietrzak, Maciej et al. (2018) AmpliSeq transcriptome analysis of human alveolar and monocyte-derived macrophages over time in response to Mycobacterium tuberculosis infection. PLoS One 13:e0198221
Lee, Sung-Ha; Ahn, Woo-Young; Seweryn, Micha? et al. (2018) Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence. BMC Genomics 19:826
Barrie, Elizabeth S; Lee, Sung-Ha; Frater, John T et al. (2018) Alpha-synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3'UTR. Mol Genet Genomic Med :
Wang, Danxin; Hartmann, Katherine; Seweryn, Michal et al. (2018) Interactions Between Regulatory Variants in CYP7A1 (Cholesterol 7?-Hydroxylase) Promoter and Enhancer Regions Regulate CYP7A1 Expression. Circ Genom Precis Med 11:e002082
Barrie, Elizabeth S; Pinsonneault, Julia K; Sadee, Wolfgang et al. (2018) Testing genetic modifiers of behavior and response to atomoxetine in autism spectrum disorder with ADHD. J Dev Phys Disabil 30:355-371
Sá, Ana Caroline C; Sadee, Wolfgang; Johnson, Julie A (2018) Whole Transcriptome Profiling: An RNA-Seq Primer and Implications for Pharmacogenomics Research. Clin Transl Sci 11:153-161
Crouser, Elliott D; White, Peter; Caceres, Evelyn Guirado et al. (2017) A Novel In Vitro Human Granuloma Model of Sarcoidosis and Latent Tuberculosis Infection. Am J Respir Cell Mol Biol 57:487-498
Luzum, J A; Pakyz, R E; Elsey, A R et al. (2017) The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems. Clin Pharmacol Ther 102:502-510
Luzum, Jasmine A; Sweet, Kevin M; Binkley, Philip F et al. (2017) CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure. Pharm Res 34:1615-1625
Pinsonneault, Julia K; Frater, John T; Kompa, Benjamin et al. (2017) Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits. PLoS One 12:e0179020

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