XGEN Profile

Expression Genetics in Drug Therapy

Abstract (Updated, November 2011)

The XGEN group is part of the OSU Program in Pharmacogenomics, supporting multiple collaborations at OSU, across the US, and abroad. The core goal of XGEN is to employ functional genomics for discovery of genetic and epigenetic factors regulating gene expression. This focus has emerged from genomics studies showing that gene regulation is a driver of evolution and that regulatory polymorphisms are highly prevalent but remain largely unexplored. XGEN has developed a comprehensive approach to the study of gene regulation, applying it to key candidate genes encoding enzymes, transporters, receptors, and signaling proteins. The results have revealed frequent regulatory variants in more than 10 genes thus far, including CYP3A4, NAT1, ABCB1, ACE, CETP, VKORC1, DAT, TPH2, MAOA, DRD2, CHRNA5, 5HT2A, OPRM1 and others. These genes are relevant to therapy of multiple diseases, including cardiovascular and CNS disorders, and cancer, enabling immediate translation into clinical studies. With use of validated regulatory polymorphisms, and collaborating with clinical scientists, we are able to test effects on clinical outcomes, either as disease risk or treatment response, often with high odds ratios. Broadening the scope of the program with use of next generations sequencing, we are now searching for regulatory variants genome-wide. A central goal of XGEN is to identify all frequent regulatory polymorphisms in therapy-related candidate genes and then test their effects singly and in interaction with each other. First results with gene-gene interactions (for example DRD2-DAT) have revealed unexpectedly strong clinical impact, directing our future work towards integration of multiple functional variants of high frequency and effect size on drug response. Availability of high-end sequencing will serve to integrate a systems biology approach for developing pharmacogenomic biomarker panels. We anticipate this approach to guide individualized therapy with improved efficacy and reduced toxicity.

XGEN Team

The Ohio State University Team

The Research Institute at Nationwide Children’s Hospital, Columbus Team

University of Florida Team

Framingham Heart Study Team

University of California, San Diego Team

University of Bari, Italy Team

Zucker Hillside Hospital team

The Ohio State University Team

The Research Institute at Nationwide Children’s Hospital, Columbus Team

PGRN Collaborations

Clinical Collaborations

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