Nanette H. Bishopric, M.D., professor of medicine, molecular and cellular pharmacology and pediatrics, and Robert J. Myerburg, M.D., professor of medicine and physiology, took part in a multicenter trans-Atlantic study of 264 patients in the U.S., Europe and Asia with this rare, but often lethal, condition.
“Although clinical risk factors for torsades de pointes have been identified, the syndrome remains unpredictable in an individual patient,” said Myerburg. “Our study examined the genetic factors to see if individuals at high risk could be identified prior to drug treatment.”
There are many genome-wide variations that indicate vulnerability to certain diseases, such as the linkage between BRCA gene mutations and breast cancer, said Bishopric. “Our hope was that by identifying all common genetic variations in these cardiac patients, we could find some that predicted risk of torsades de pointes,” she added.
Myerburg and Bishopric were co-authors of the study, “Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes,” which was published recently in PLOS ONE, an open access peer-reviewed scientific journal published by the Public Library of Science. Vanderbilt University and the UM Miller School of Medicine coordinated the U.S. aspects of the study, which was supported by a grant from the Fondation Leducq (Trans-Atlantic Network of Excellence “Alliance Against Sudden Cardiac Death”). The study had 35 co-authors from 15 research centers in the U.S., Europe and Asia.
Torsades de pointes is a potentially lethal arrhythmia that is heralded by a prolonged QT interval on the electrocardiogram. QT prolongation and TdP can be caused by inheritance of rare gene mutations that cause malfunction of the electrical currents in the heart muscle. Genetic studies have identified hundreds of mutations that associate with this disorder, called long QT syndrome (LQTS). “Now we know how to screen for those who carry a relevant LQTS variant and those who do not,” said Myerburg.
However, a number of drugs, including some commonly used antibiotics, can lengthen the QT interval, and also can be associated with torsades de pointes, in a syndrome called acquired LQTS. It is known that the risk of drug-induced QT prolongation and TdP is higher in patients with inherited long QT syndrome. “The issue at hand in this study was to identify additional, more common genetic variants that could predispose to drug-induced torsades de pointes in the general population,” said Myerburg. “Since the susceptibility to acquired LQTS now appears to run in families as well, it was important to continue looking at the genetic factors.”
The multicenter study compared genome-wide DNA variations of patients developing torsades de pointes on therapeutic medications with patients who had been exposed to similar drugs but did not develop arrhythmia, and with a third control group from the general population. The study focused on common variants, meaning that they can be found in 10 to 20 percent of the population.
After reviewing and analyzing vast amounts of genetic data, the researchers found no common genetic variants that could predict which patients might be at high risk for torsades de pointes, according to Bishopric. “It’s possible that multiple, individually rare genetic variants are responsible for the drug-induced form of the syndrome,” she said. “It’s also possible that there is an additive effect of two or more variants, or that clinical factors affect the way these genes are expressed in individual patients.”
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