For some people, a cardiac side effect of many drugs could be a real killer. In a first step toward identifying and protecting those individuals, researchers have found some of the common genetic variations that subtly influence the time it takes the heart muscle to relax electrically between beats.
Between each contraction, the heart normally relaxes for less than half a second, known as the QT interval on electrocardiogram recordings. Longer QT intervals raise the risk of uncontrolled rapid heartbeat and of sudden cardiac death.
Many different drugs can cause longer QT intervals, said Christopher Newton-Cheh, a cardiologist at Massachusetts General Hospital. The side effect is clinically significant for about 80 currently marketed drugs, including a commonly prescribed antibiotic. The effect has resulted in some therapeutics being pulled off the market and others being blocked from reaching it, he said.
With more research, genetic factors could turn out to be good predictors of sudden cardiac death in general or specifically in response to QT-prolonging medications, said Newton-Cheh, HMS assistant professor of medicine. The information could prevent vulnerable people from harmful exposures and allow others access to otherwise beneficial drugs.
In a meta-analysis of three genomewide association studies in 13,685 people of European ancestry, the researchers found 14 variants in 10 genes that explained about six percent of the variation in QT interval between individuals. Five of the genes were new and previously unrecognized to have a role in QT physiology. The findings are reinforced by overlapping results reported by another team. Both studies were published on March 22 in the online Nature Genetics.
While these findings only skim the surface of the genetic underpinnings of QT interval differences in the general population, “the collective effect of the 10 genes is already operating at a scale comparable to or exceeding the known drugs that influence the QT interval or have never made it to market because of the effect,” said coauthor Paul de Bakker, HMS assistant professor of genetics at Brigham and Women’s Hospital.
Since the paper was published, Newton-Cheh has received a dozen requests from worried people to evaluate genomes for sudden cardiac death or drug toxicity, but the public health relevance of the work is unknown and untested. “Other research has shown an absolute proof of a link between QT and sudden cardiac death,” de Bakker said. “We have only established a link between genetic variation and QT. We are now testing how the variants influence sudden cardiac death directly.” Further clinical trials will be required to validate the hypothesis.
Students may contact Christopher Newton-Cheh at cnewtoncheh@chgr.mgh.harvard.edu or Paul de Bakker at pdebakker@rics.bwh.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: the National Institutes of Health, Doris Duke Charitable Foundation, and Burroughs Wellcome Fund; the content of the work is the responsibility solely of the authors
