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.
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.
|Kitzmiller, Joseph P; Luzum, Jasmine A; Baldassarre, Damiano et al. (2014) CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort. Pharmacogenet Genomics 24:486-91|
|Talameh, Jasmine A; Kitzmiller, Joseph P (2014) Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants. J Pharmacogenomics Pharmacoproteomics 5:|
|Mates, Jessica M; Kumar, Surender B; Bazan, Jose et al. (2014) Genotypic and phenotypic heterogeneity in the U3R region of HIV type 1 subtype C. AIDS Res Hum Retroviruses 30:102-12|
|Jiang, Yao; Wang, Jiang; Rozewski, Darlene M et al. (2014) Sensitive liquid chromatography/mass spectrometry methods for quantification of pomalidomide in mouse plasma and brain tissue. J Pharm Biomed Anal 88:262-8|
|Hook, Vivian; Brennand, Kristen J; Kim, Yongsung et al. (2014) Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Reports 3:531-8|
|Phelps, M A; Stinchcombe, T E; Blachly, J S et al. (2014) Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses. Clin Pharmacol Ther 96:182-91|
|Barrie, Elizabeth S; Weinshenker, David; Verma, Anurag et al. (2014) Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. Circ Res 115:1017-25|
|Smith, Ryan M; Banks, Wesley; Hansen, Emily et al. (2014) Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder. Autism Res 7:459-67|
|Sadee, Wolfgang; Hartmann, Katherine; Seweryn, Micha? et al. (2014) Missing heritability of common diseases and treatments outside the protein-coding exome. Hum Genet 133:1199-215|
|Wang, Danxin; Poi, Ming J; Sun, Xiaochun et al. (2014) Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity. Hum Mol Genet 23:268-78|
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