Two international research studies, both led by investigators affiliated with Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, have uncovered new information about genes that may increase the risk of serious cardiac arrhythmias. The studies recently received back-to-back advance online publication in Nature Genetics and Nature Methods.
The Nature Genetics report identifies several new gene regions associated with variations in the QT interval – a stage in the heart's electrical cycle that, if prolonged, increases the risk of drug-induced arrhythmias and sudden cardiac death. A surprising finding of that paper was the extent to which genes involved in calcium signaling influence the QT interval, the time from electrical activation of heart cells, which stimulates contraction, to the end of electrical relaxation.
"We have known that calcium signaling is critically important in regulating the contraction of muscle cells that generates the heartbeat," says Christopher Newton-Cheh, MD, MPH, of the MGH Center for Human Genetic Research and Cardiovascular Research Center, corresponding and co-senior author of the Nature Genetics report. "But finding that calcium is also involved in resetting the heart after each beat was a total surprise and represents a new avenue to pursue in the causes of arrhythmias."
The Nature Methods paper describes a novel approach to analyze and map the protein networks that drive cardiac repolarization – the biological process disturbed in arrhythmias. By integrating this network with results from the Nature Genetics paper, the researchers were able to pinpoint specific genes involved in the biology of cardiac repolarization, which would have been challenging to accomplish from the genetics alone. This approach also allowed identification of three genetic variants involved in arrhythmias that had been missed in earlier studies.
"Like people, genes like to work in groups, and we used the newest technologies in genomics and proteomics to derive the working group of genes involved in processes that coordinate the beating of the heart and, when malfunctioning, can cause arrhythmias or sudden cardiac death," says Kasper Lage, PhD, of the MGH Department of Surgery and the Analytic and Translational Genetics Unit, co-senior author of the Nature Methods paper. "Potassium signaling is known to be involved in cardiac repolarization, but our network analysis also pointed to a calcium pump and two proteins regulating this pump as culprits. Finding that calcium signaling also plays a role in repolarization was an unexpected and intriguing discovery."
The Nature Genetics paper describes a meta-analysis of genome-wide association studies (GWAS) involving more than 100,000 individuals that identified 35 common gene variant locations – 22 for the first time – associated with alterations in the QT interval. Identifying a previously unknown role for calcium signaling in the QT interval constitutes, according to Newton-Cheh, "a quantum leap in our ability to study one of the major causes of death in people with heart failure – which is well known to involve calcium abnormalities – and an important cause of fatal arrhythmias that occur as a side effect of several medications."
The team behind the Nature Methods paper used quantitative interaction proteomics, which determines not just whether two proteins interact but the extent of their interaction, to map in mouse hearts networks of proteins encoded by known repolarization genes and confirmed those findings in frog eggs and in zebrafish. Integrating those results with the GWAS analysis revealed that 12 genes in locations identified by the Nature Genetics study encoded proteins in the network described in the Nature Methods paper, providing a strong link between genes well-established to cause rare sudden death syndromes and genes associated with common QT-interval variation in the general population.
"These studies are more than the sum of their parts, because their integration of proteomic networks with genomic findings catalyzes the interpretation of the genetic findings to reveal new biology relevant to dangerous arrhythmias," says Lage. "We also provide a general methodology to interpret genetic data using tissue-specific proteomics networks. Importantly, our analysis also shows that we are able to use computational algorithms such as one developed by Elizabeth Rossin, a co-lead author of our paper, to functionally interpret large genetic association studies.
"The genetics communities' worldwide now use Elizabeth's tools," he adds, "and our study rigorously follows up and confirms their predictions. This is an important result because the ongoing revolution in methods of sequencing genomes and mapping genetic variation has produced massive amounts of genetic data, and we need scalable computational ways to interpret these datasets to guide biological insight and therapeutic intervention. Our study proves the predictions made by our computational tools, thus supporting their ability to provide insight into the molecular networks perturbed by genetics in many common complex disorders."
The consortium behind the Nature Genetics study involved more than 230 investigators at more than 180 institutions in 17 countries. In addition to Newton-Cheh, an assistant professor of Medicine at Harvard Medical School (HMS) and associate member of the Broad Institute, co-senior authors of the Nature Genetics study are Paul de Bakker, PhD, University Medical Center, Utrecht, the Netherlands; Arne Pfeufer, MD, Institute of Human Genetics, Munich, Germany, and Michael Ackerman, MD, PhD, Mayo Clinic. MGH co-authors include co-lead author Sara Pulit, Elizabeth Rossin, MD, PhD, and Mark Daly, PhD.
Along with Lage, an assistant professor at HMS and associate member of the Broad, co-senior authors of the Nature Methods paper are de Bakker and Jesper Olsen, PhD of the University of Copenhagen, Denmark. Additional co-authors include co-lead authors Alicia Lundby, University of Copenhagen, and Elizabeth Rossin, MD, PhD, MGH and Broad Institute; Newton-Cheh and Daly; and David Milan, MD, and Patrick Ellinor, MD, PhD, MGH Cardiology. Both studies were supported by a large number of funders in the U.S. and Europe.