Dr. Dan Roden is the principal investigator of the new grant. (photo by Dana Johnson)
Medication response target of new study
It’s a simple fact that we all accept-not everyone responds to medications the same way. We know that a cold remedy that makes one person jittery can put the next to sleep; we realize that a pain reliever that works wonders for a friend may not touch our pain at all.
Investigators have recognized and studied this variability in drug responses for a long time, said Dr. Dan M. Roden, William Stokes Professor of Experimental Therapeutics, Medicine, and Pharmacology. And they are now poised to extend these studies to the genetic level, “to understand how the genetic variants that make us all different from each other contribute to our differences in drug responses.”
This burgeoning research area, called “pharmacogenetics,” promises to usher in an era of tailor-made prescriptions-medicines carefully matched to patients’ personal genetic codes, Roden said.
A newly awarded four-year, $11.2 million grant from the National Heart, Lung, and Blood Institute places Vanderbilt among a select group of institutions leading the pharmacogenetics charge. The grant, part of a National Institutes of Health initiative to understand how genetic makeup influences drug response, makes Vanderbilt one of 13 members of the Pharmacogenetics Research Network and Knowledge Base. Members of the research network store data in a shared information library that is freely accessible to the scientific community (www.pharmgkb.org).
Each pharmacogenetics network member has a specific area of specialization-Vanderbilt is the arrhythmia center. Efforts at Vanderbilt will focus on discovering the genetic variants that affect electrical activity in the heart and understanding how those variants influence responses to antiarrhythmic drug therapy, said Roden, the principal investigator of the new grant.
“One of the striking things about drugs that regulate heart rhythm is the spectrum over which they work,” Roden said. “There are patients for whom a dose of medication makes a heart rhythm problem melt away and others for whom a dose of the same medication causes a catastrophic, perhaps even life-threatening side effect. We need to find a way to distinguish who’s going to do well and who’s going to do poorly so that we can target the right drug to the right patients.”
The answers, scientists believe, lie in tiny single-letter changes littered among the three billion letters that spell out the human genetic code. These SNPs (single nucleotide polymorphisms, “snips”) could affect any number of proteins that influence drug action. The proteins that process the drug, the proteins targeted by the drug, and the proteins that set the biological context of the drug-target interaction are all candidates for variation, Roden said.
Investigators hope to identify the collections of SNPs that will determine—for a given drug—who will benefit, who will not, and who will suffer serious side effects. Prescribing medications based on genetic profiles would theoretically eliminate the adverse drug reactions that, according to the NIH, currently send over two million Americans to the hospital and kill 100,000 each year.
The process of identifying SNPs and correlating them with drug responses is a “highly collaborative, interactive science,” Roden said. “We will need a large team of physicians and research nurses collecting data, sophisticated methods for acquiring and analyzing DNA samples, and advanced statistical analysis tools to understand the linkage between many different variants in the human genome and the various kinds of abnormal heart rhythms that we study.”
The investigators will target four broad areas of arrhythmia therapy in their search for genetic variants that predict drug responses. They will study patients who develop abnormal heart rhythms as a consequence of antiarrhythmic therapy, patients who develop atrial fibrillation following cardiac surgery, variability in dose requirements for the blood-thinning drug Coumadin, and variability in the risk for sudden death, which kills up to 500,000 Americans each year, Roden said.
Roden and colleagues will use a “candidate gene approach” to identify SNPs that affect electrical activity in the heart. They will use current understanding of the physiology of a cardiac muscle cell to identify candidate genes—between 100 and 500—which warrant further exploration.
“We understand many of the molecular players that perform a highly choreographed ballet to produce cardiac electrical activity,” Roden said. “A drug may target one participant of that ballet, but it is the genomic variability in the whole system that modulates the response to that drug.
“It’s probably not possible for us to list all the participants, but we can make a reasonable list of genes that may play a role in setting the biologic context in which the drug-target interaction occurs.”
The reality of customized drug prescriptions lies at least 10 or more years in the future, Roden said. “After relating SNPs to clinical outcomes, we will need to validate the results and be sure that when we tell people they should or should not take a particular drug, that it makes a difference to their health care.
“Personalized medicine is a very appealing prospect, and one that we’re delighted to be a part of. It’s going to take a lot of work, a lot of interesting work, to realize the vision.”
Collaborators on the new grant include Dr. Alfred L. George Jr., Jonathan L. Haines, Ph.D., Dr. Constantin Aliferis, Dr. Jeffrey R. Balser, Dr. Nancy J. Brown, Dr. Brian S. Donahue, Dr. Richard B. Kim, Sabina Kuperschmidt, Ph.D., Dr. Randolph A. Miller, Jason H. Moore, Ph.D., Dr. C. Michael Stein, Dr. Alastair J. J. Wood, and Tao Yang, Ph.D.