Sep. 12, 2001 Whether subtle genetic variations among patients with high blood pressure (hypertension) can predict treatment effectiveness is the focus of a new research effort at the University of California, San Diego (UCSD) School of Medicine. This is among the nation’s first federally-funded studies in the emerging field of individualized medicine or "pharmacogenomics," with therapy tailored to a person’s own genetic profile.
Funded by a $11.6 million, four-year grant from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH), the project will team UCSD with Celera Genomics, the company that recently identified and published the sequence of the human genome.
“Why some people respond to blood pressure medications and others don’t has always puzzled physicians,” said project director Daniel T. O’Connor, M.D., UCSD professor of medicine, and a hypertension and kidney disease specialist at UCSD and the Veterans Affairs San Diego Healthcare System. “We believe that a substantial part of that variability is the result of differences in genes that either metabolize drugs or are the target of drugs.”
The goal of pharmacogenomics research is to move beyond the "one-size-fits-all" approach to drug therapy and allow the development of individualized treatment plans based on genetic profiles. Using genetic indicators, physicians and pharmacists can determine in advance which drugs will work best for specific individuals and which are more likely to cause harmful side effects, and prescribe the most effective therapies.
“This research represents the future of medicine and how we will manage disease in the 21st century,” said Edward W. Holmes, M.D., vice chancellor for Health Sciences and dean, UCSD School of Medicine. “With ongoing investigations in the new scientific discipline of pharmacogenomics, we hope to better understand how individual variations in patient DNA can influence disease progression and treatment response.”
While most humans share 99.9 percent of the same genetic sequence, scientists are discovering differences located within the genome (the DNA or hereditary material) in cells throughout the body.
For the complex task of identifying and genotyping genetic variations, called single nucleotide polymorphisms (“SNPs,” pronounced “snips”), the Genomics Core for this program will be run by Celera Genomics, the company that recently identified and published the sequence of the human genome. UCSD will collect DNA samples from more than 800 normal and hypertensive patients and send those samples to Celera for SNP identification and genotyping.
“We are very pleased that Celera and the clinical researchers at UCSD can work together to begin understanding how variations in the human genome can help explain why these kinds of differences exist and how to harness them so physicians can treat individual patients and not statistical averages,” said J. Craig Venter, Ph.D., Celera’s president and chief scientific officer.
The UCSD team will begin by studying human subjects, monitoring changes in blood flow, blood pressure, release of adrenaline and other indicators. DNA from these individuals will be sent to Celera, which will locate and genotype the SNPs within each individual’s genome. Then, UCSD researchers will look at the association between identified genetic variants and particular drug responses in each individual.
“Once we discover those particular variants that seem to be the culprits, we’ll study them in test tubes,” O’Connor said. “Further studies in mice will help us understand the mechanism whereby the genetic variant gives rise to a specific trait, or drug response.”
Finally, clinical trials will be conducted to determine if specific SNPs can predict therapeutic drug responses.
All over the world, research universities and biotechnology companies are searching for new SNPs and trying to determine their function within the body. Much of that research focuses on studies of genes that metabolize drugs, i.e. how the body absorbs medication and eliminates it from the body. The UCSD effort focuses on what happens after a blood pressure drug reaches its target gene within the body.
The UCSD pharmacogenomics project is part of the National Institute of General Medical Sciences NIH Pharmacogenetics Research Network and Knowledge Base. This nationwide research effort oversees investigations at UCSD and 13 additional research centers, with emphasis on a variety of medical conditions including cardiovascular disease, cancer prevention and treatment, asthma, and depression.
The NIGMS notes that at the heart of their Pharmacogenetics Research Network is a shared information library called “PharmGKB,” into which network researchers deposit results they collect. Contents of the library will be accessible to all scientists, with the goal of forging new links between gene variation and drug response.
In addition to O’Connor, UCSD researchers who will participate in the pharmacogenomics studies are Paul Insel, M.D., professor of pharmacology and medicine; Lewis J. Rubin, M.D., professor of medicine; Jason X. Yuan, M.D., Ph.D., associate professor of medicine; Robert J. Parmer, M.D., professor of medicine; Michael G. Ziegler, M.D., professor of medicine; Nicholas Schork, Ph.D., professor of psychiatry; Palmer W. Taylor, Ph.D., professor and chair, Department of Pharmacology; Sushil K. Mahata, Ph.D., associate professor of medicine; Anthony Wynshaw-Boris, M.D., Ph.D., assistant professor of neurosciences and pediatrics; and John Ross, M.D., professor of medicine. Additional researchers include Emily S. Winn-Deen, Ph.D., director of SNP R&D at Celera Genomics and Michael Lipkowitz, M.D., Mt. Sinai School of Medicine.
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