Oncology
Intersection of Cancer Pathways Mapped
Mental Health
Survey Finds Iraqi Minds Resilient Despite War
Biomedical Engineering
Bacterial Viruses Boost Antibiotic Action
Gene Study First Step to Predicting Cardiac Drug Toxicity
Database Displays Mutations for Drug Resistance in TB
Five in Community Win HHMI Early Career Awards
Funding Renewed for Infectious-disease Research Center
Proceedings of the HMS Faculty Council
Alumna Called to Lead Indian Health Service
Dubai Harvard Foundation Funds International Collaborations
Harvard Catalyst Announces Pilot Grant Recipients
HST Student Wins Weintraub Award
Plunge on the Slopes Gives Fourth-year Jump on Internship
RESEARCH BRIEFS
Gene Study First Step to Predicting
Cardiac Drug Toxicity
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
Database Displays Mutations for Drug Resistance in TB
Hoping to spur better diagnostic tools and new therapies for drug-resistant tuberculosis, HSPH researchers and their colleagues have put together a comprehensive open-access database of drug resistance mutations.
Increasing resistance to the mainstay drugs isoniazid and rifampicin and also to many of the second-line options threatens global efforts to control TB. Diagnosis everywhere now depends on culturing the slow-growing organism, which is nearly impossible in resource-poor settings, said senior author Megan Murray, HSPH associate professor of epidemiology.
“It takes so long that by the time people are diagnosed, they have died or transmitted it to others, or both,” she said. “Part of the goal is to develop cheap and rapid diagnostics.”
The TB Drug Resistance Mutation Database (http://www.tbdreamdb.com) is
divided into two parts, said creator and curator Andreas Sandgren, a postdoctoral
fellow. The first part is a collection of unique mutations associated with
resistance to specific drugs culled from a systematic review of hundreds
of scientific papers.
For the second part, Sandgren extracted the relative frequency of the most
common mutations from 10 high-quality publications, which is helpful for
geographic surveillance and diagnostic strategies, he said.
The database started as a tool to support two major projects in the Murray group, the first a whole-genome sequencing of three dozen drug-resistant TB strains from patients around the world and the second an in-depth analysis of putative drug-resistance genes in several thousand clinical samples. This work is in progress. Published results will be added to the database.
“After we created it, we realized it would be useful for the rest of the TB research community,” said Sandgren, first author of the paper announcing the resource in the February PLoS Medicine.
“So many people need to use these data,” said Murray. “To waste effort and time to recompile them again and again is crazy. This can really change the way research occurs. It means people can bring their own ideas to research the database without having to do the actual work of compiling it.”
As of September, the database contained 946 unique mutations associated with seven different drug classes and spread over 36 genes, two intergenic/promoter regions, and one ribosomal RNA coding region. “We set up strict criteria to make sure we can trust the data,” said Sandgren, who will add data as newly published research warrants.
Sandgren will continue to curate the database and collaborate on the project when he returns to the Karolinska Institute to continue his postdoctoral studies.
Students may contact Megan Murray at mmurray@hsph.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The Ellison Foundation. Sandgren was also funded through a postdoctoral stipend from the Swedish Society for Medical Research/Stiftelsen för Medicinsk Forskning and Stiftelsen Olle Engqvist Byggmästare; the content of the work is the responsibility solely of the authors