A new study has identified several common genetic variants related to a risk factor for sudden cardiac death. The report receiving early online release in the journal Nature Genetics identifies variants in genes, some known and some newly discovered, that influence the QT interval measured on the electrocardiogram (EKG) performed routinely in doctors' offices. These findings could eventually help to prevent sudden cardiac death and arrhythmia by limiting the use of medications that affect QT interval in people with these variants.
The QT interval is the time from the beginning of electrical activation of the heart to the end of electrical relaxation. "It is well established that prolongation of the QT interval in the general population is a potent and heritable risk factor for sudden death," said Christopher Newton-Cheh, MD, MPH, of the Massachusetts General Hospital (MGH) Center for Human Genetic Research and Cardiovascular Research Center (CVRC) and lead author of the Nature Genetics article. "In addition, QT prolongation results from medications leading to drug-induced cardiac arrhythmias and sudden death. This is a cardiotoxic side effect of scores of medications in widespread use and has been a major barrier to the development of novel drugs. From studies of families with congenital long-QT syndrome, we know that rare mutations with strong effects on ion channel function lead to QT prolongation and sudden death. But the common genetic basis for QT prolongation has been very difficult to establish."
To search for QT-associated variants, the investigators formed the QTGEN consortium, assembling more than 13,000 individuals from three studies – including the National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study. All individuals had undergone testing of hundreds of thousands of common gene variations called single-nucleotide polymorphisms (SNPs).
By pooling results from the three studies, investigators identified 14 common variants in 10 different gene regions (some regions had more than one variant) that were related to QT interval duration. A separate companion paper from the QTSCD consortium in the same issue of Nature Genetics – led by Arne Pfeufer, MD, of the Technical University of Munich and Aravinda Chakravarti, PhD, Johns Hopkins University School of Medicine – included more than 15,000 individuals from Europe and the US. This independent study strongly confirmed 12 out of 14 of the QTGEN variants and identified two additional gene regions. "We were very reassured to see such strong replication in two independent studies" said Newton-Cheh.
The QTGEN investigators examined the effect of a genotype score comprised of all 14 variants tested together. The top 20 percent of the population with the highest genotype scores had 160 to 210 percent higher risk of prolonged QT interval compared to the 20 percent of the population with the lowest scores. They also had around 10 millisecond longer QT intervals, which is approximately the degree of QT interval prolongation observed for some drugs pulled from the market for arrhythmias.
"While it is commonly a combination of risk factors that contributes to drug-induced arrhythmias – such as older age, female sex, use of other medications, or heart disease – it is certainly possible that common genetic variants will add incrementally to risk prediction," said Newton-Cheh. "It's currently premature to advocate screening gene variants for risk assessment, but someday it may be possible to identify individuals who are at particularly high risk and should avoid such medications."
Newton-Cheh adds, "It's likely that many more genes will be found to contribute to changes in QT interval, and the real challenge will be understanding the mechanism behind their effects. Five of the gene regions we identified had never before been implicated in QT interval physiology and these genetic observations may thus provide key insights into normal and abnormal human biology." He is an assistant professor of Medicine at Harvard Medical School.
Support for the Nature Genetics study included grants from the National Institutes of Health, the Doris Duke Charitable Foundation, the Burroughs Wellcome Fund, and the Netherlands Organization for Health Research and Development. Co-authors of the paper are Peter Noseworthy of Massachusetts General Hospital Cardiology Division; Paul de Bakker of Brigham and Women's Hospital; Xiaoyan Yin, Christopher O'Donnell and Martin Larson of National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study; Mark Eijgelsheim, Karol Estrada, Fernando Rivadeneira, Jan Kors, Jacqueline Witteman, Albert Hofman, André Uitterlinden and Bruno Stricker of Erasmus Medical Center; Kenneth Rice, Joshua Bis, Kristin Marciante, Nona Sotoodehnia, Nicholas Smith, Susan Heckbert, Bruce Psaty and Thomas Lumley of Washington University; and Jerome Rotter of Cedars-Sinai Medical Center.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
Journal
Nature Genetics