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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01GM092655-05
Application #
8681467
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Long, Rochelle M
Project Start
2010-07-16
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
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
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
Sweet, K; Sturm, A C; Schmidlen, T et al. (2017) EMR documentation of physician-patient communication following genomic counseling for actionable complex disease and pharmacogenomic results. Clin Genet 91:545-556
Sá, Ana Caroline C; Sadee, Wolfgang; Johnson, Julie A (2017) Whole Transcriptome Profiling: An RNA-Seq Primer and Implications for Pharmacogenomics Research. Clin Transl Sci :
Shahin, Mohamed H; Sá, Ana C; Webb, Amy et al. (2017) Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response. Circ Cardiovasc Genet 10:
Kitzmiller, J P; Luzum, J A; Dauki, A et al. (2017) Candidate-Gene Study of Functional Polymorphisms in SLCO1B1 and CYP3A4/5 and the Cholesterol-Lowering Response to Simvastatin. Clin Transl Sci 10:172-177
Barrie, Elizabeth S; Hartmann, Katherine; Lee, Sung-Ha et al. (2017) The CHRNA5/CHRNA3/CHRNB4 Nicotinic Receptor Regulome: Genomic Architecture, Regulatory Variants, and Clinical Associations. Hum Mutat 38:112-119
Schmidlen, Tara J; Scheinfeldt, Laura; Zhaoyang, Ruixue et al. (2016) Genetic Knowledge Among Participants in the Coriell Personalized Medicine Collaborative. J Genet Couns 25:385-94
Hartmann, Katherine; Seweryn, Micha?; Handelman, Samuel K et al. (2016) Non-linear interactions between candidate genes of myocardial infarction revealed in mRNA expression profiles. BMC Genomics 17:738

Showing the most recent 10 out of 74 publications