In a new study, researchers at Mount Sinai School of Medicine have taken a major step toward the ability to predict adverse drug reactions, using genetic, cellular, and clinical information to learn why some medicines cause heart arrhythmias in patients. Published in the April 20 issue of the journal Science Signaling, the new framework described in the study could potentially be applied to the study of medications that treat other diseases and disorders such as epilepsy and autism.
Researchers have learned over the last decade that human genetic make-up contains slight variations that can alter individual responses to medications. Led by Ravi Iyengar, PhD, Dorothy H and Lewis Rosenstiel Professor and Chair, Department of Pharmacology and Systems Therapeutics, and Director, Systems Biology Center, Mount Sinai School of Medicine, the research team was able to harness genetic information in a way that can detect and predict a drug's adverse effect, such as arrhythmias.
"Arrhythmias are side effects in so many different classes of drugs, for diseases ranging from insomnia to epilepsy," said Dr. Iyengar. "By identifying the mechanism causing these adverse events, we can hopefully predict them in other drugs, and help physicians tailor treatment for patients."
Dr. Iyengar's team wanted to find out why certain drugs caused arrhythmias similar to those seen in people with Long-QT Syndrome (LQTS), a congenital heart defect that causes changes in the electrical activity of the heart. These arrhythmias are caused by mutated genes, and can be dangerous and potentially fatal. Scientists have identified 13 genes associated with LQTS, and the team hypothesized that the drugs that cause arrhythmias act upon the genes' proteins, as well as partnering and neighboring proteins.
Using computation, researchers learned that the proteins formed their own grouping, or a so-called "neighborhood." Certain proteins in this neighborhood overlapped with other neighborhoods associated with other diseases like congestive heart failure, insomnia, autism, schizophrenia, and epilepsy. This discovery showed that several diseases share common molecular features, which could mean people with these conditions are susceptible to other diseases that have proteins in overlapping neighborhoods.
Dr. Iyengar's team then cross-referenced their framework with adverse event reporting databases, including that of the U.S. Food and Drug Administration, to find that drugs known to cause the electrical malfunction leading to arrhythmia do act on proteins within the same local neighborhood. The framework identified drugs from disease categories ranging from cancer to antifungal treatments that may pose risk for arrhythmias.
"Now that we know our framework may apply across many disease categories, we hope that physicians will eventually be able to use systems biology to help find the best treatment for their patients," said Dr. Iyengar. "These data will also help us improve drug design and development. We look forward to further pursuing this exciting advance."
Dr. Iyengar directs one of the National Centers for Systems Biology supported by the National Institute of General Medical Sciences of the National Institutes of Health, which funded this research.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of few medical schools embedded in a hospital in the United States. It has more than 3,400 faculty in 32 departments and 15 institutes, and ranks among the top 20 medical schools both in National Institute of Health funding and by U.S. News & World Report. The school received the 2009 Spencer Foreman Award for Outstanding Community Service from the Association of American Medical Colleges.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2009, U.S. News & World Report ranked The Mount Sinai Hospital among the nation's top 20 hospitals based on reputation, patient safety, and other patient-care factors. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 530,000 outpatient visits took place.
For more information, visit www.mountsinai.org.
Journal
Science Signaling