In the emerging era of personalized health care, use of genetic information has vast promise in reducing toxicity and improving efficacy of drug therapy. This applies to drugs already in routine use and to novel drugs emerging from the discovery pipeline.
The Pharmacogenomics Program at The Ohio State University Medical Center aims to find biomarkers that guide effective treatment of individual patients. Directed by Wolfgang Sadée, Dr.rer.nat., the program has developed a novel approach to finding genetic variations in candidate genes suspected of playing a significant role either as drug targets/modifiers or as disease risk factors. The research areas in the Pharmacogenomics Core Laboratory include central nervous system disorders (addiction, schizophrenia and depression, abnormal cognitive function), cardiovascular disease (hypertension), cancer, autoimmune diseases (multiple sclerosis) and pharmacokinetics/pharmacodynamics (drug absorption, distribution, metabolism, excretion/elimination (ADME), and drug targets).
Sadée’s laboratory has developed a large-scale genotyping methodology to identify single nucleotide polymorphism (SNP) for several hundred genes that can be potentially used as biomarkers for drug therapy and disease prediction. His recent studies have shown that functional SNPs of the ACE (angiotensin-converting enzyme) are highly linked to allelic and total mRNA expression of ACE. These functional SNPs were strongly associated with clinical outcomes in hypertensive coronary artery disease (CAD) patients, prominently in African-American populations (collaboration with Julie Johnson, PharmD, University of Florida). These studies provide important information not only in identifying risk factors for CAD but also potentially in predicting therapy response to ACE inhibitors. In another study, Sadée’s laboratory has recently identified novel polymorphisms that regulate the expression and splicing of the dopamine D2 receptor, a key component of dopaminergic neurotransmission. These genetic variants were then shown to affect cognitive processing and memory functions in human subjects (collaboration with Alessandro Bertolino, MD, PhD, University of Bari), and they could play a role in response to antipsychotic therapy.
In addition, the Sadée lab has developed a genotyping assay that can identify genetic variants for genes that are involved in pharmacokinetics. Results from this ADME SNP panel are followed by analysis of the underlying molecular genetic mechanisms, and are further assessed for prediction of an individual’s response to drug therapy. Taken together, ongoing studies in The Ohio State University Medical Center’s Pharmacogenomics Program will provide important information in guiding clinicians to tailor treatment for each individual, by maximizing efficacy and minimizing adverse effects of drug therapy.
References
Sadée W and Dai Z Pharmacogenetics/genomics and personalized medicine. Hum Mol Genet, 2005; Oct 15;14 Spec No. 2:R207-14.
Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee ML, Xiao T, Papp A, Wang D, Sadée W. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci U S A. 2007;104(51):20552-7.
Johnson AD, Gong Y, Wang D, Langaee TY, Shin J, Cooper-DeHoff RM, Schork NJ, Shriver MD, Binkley P, Pepine CJ, Johnson JA, and Sadée W Novel promoter polymorphisms in ACE (antiotensin I-converting enzyme) associated with clinical outcomes in hypertension. Manuscript submitted.
To locate more information pertaining to the above referenced articles please visit the PubMed database.