omation mbers - Society for Laboratory Automation and Screening

2:30 pm Thursday, February 5 Clinical – Pharmacogenomics Room C1
Stan Lilleberg
Transgenomic, Inc.
11 Firstfield Road, Suite E
Gaithersburg, Maryland 20878
slilleberg@transgenomic.com
In-depth Genetic Variation Screening Using DHPLC: A Valuble Component of the Drug
Development Process
The genomics revolution has forever altered the landscape of pharmaceutical research and development. In
addition to the discovery of new potential drug targets, the number of mutations and polymorphisms identified
within individual genes is escalating. Since the biological impact of each individual genetic variation depends
on its location and specific sequence alteration, there will be a constant requirement for sensitive and accurate
methods to scan genes of interest for new, and often low-level, genetic variation. Denaturing high performance
liquid chromatography (DHPLC) is a new technology used in the discovery of genetic variations in the form of
mutations that include single base substitutions or single nucleotide polymorphisms (SNPs), as well as small
deletions or insertions. These genetic variations can be routinely detected by DHPLC gene scanning at the germline
and somatic levels. Epigenetic alterations such as changes in DNA methylation status at defined loci can also
be assessed using DHPLC-based methodology. The biological impact of these genetic variations depends on the
location and identity of the DNA sequence alteration. The discovery of functionally relevant genetic variations can
be exploited throughout the drug discovery and development process. Examples of the application of DHPLC for
sequence variant detection will be presented and discussed, with an emphasis on target validation by candidate
gene scanning, mutation detection in disease pathway genes, and the discovery of therapeutically significant
genetic variants associated with drug metabolism and resistance. In-depth genetic variation screening using
DHPLC technology has accelerated the discovery of novel variants in a multitude of genes, contributing to the
understanding of disease pathogenesis and future directions of drug development.
3:00 pm Thursday, February 5 Clinical – Pharmacogenomics Room C1
Elvan Laleli-Sahin
Medical College of Wisconsin-Milwaukee
Pathology Department
8701 Watertown Plank Road
Milwaukee, Wisconsin 53226
elvan@mcw.edu
121
Co-Author(s)
Paul Jannetto,
Steven H. Wong
Utilization of Pharmacogenomics in Patient Care for Pain Management Clinics and Poison
Control Centers
One direct application of the genetic information generated with in the last decade has been pharmacogenetics;
science of explaining genetic based pharmacokinetic and pharmocodynamic variability among individuals. Use
of pharmacogenetics for evaluating why certain therapies fail will be a direct and rapid clinical application. The
enzyme family (cytochrome P450 – CYP) responsible for the first phase metabolism of a foreign compound, shows
polymorphisms that correlate with an individual’s phenotype in response to a given drug. The phenotype can
vary from no response to therapy to severe adverse drug reactions and even death due to over dose. CYP 2D6,
is the enzyme responsible for metabolism of almost one quarter of prescription drugs, including analgesics. Pain
management of chronic pain patients varies due to the subjective nature of pain along with the genetic variability of
drug metabolizing enzymes, especially CYP 2D6. Single nucleotide polymorphisms (SNP’s) and deletion mutations
within this gene have been shown to correspond with poor metabolizer phenotype. Pharmacogenetics possesses
the potential to aid in efficient therapy for chronic pain patients that are proven to be difficult to manage cases. Our
ongoing studies have identified 25% prevalence for intermediate metabolizers. In addition there is good correlation
of genotype and response to therapy. Extensive metabolizer individuals showed no adverse reactions while an
intermediate metabolizer, with normal kidney and liver functions, showed adverse side-effects to tramadol therapy.
PODIUM ABSTRACTS