Study reveals new information about genes that may increase the risk of cardiac arrhythmias
Two international studies, both conducted by investigators affiliated with Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, have discovered new information about genes that may increase the risk of serious cardiac arrhythmias. Studies have recently received back-to-back advance online publication Nature Genetics and Nature Methods .
The Nature Genetics report identifies several new gene regions associated with changes in QT interval - a step in the electrical cycle of the heart which, if prolonged, increasing the risk arrhythmias induced by drugs and sudden cardiac death. A surprising discovery of this document was the extent to which genes involved in calcium signaling influences the QT interval, time for electrical activation of the heart cells, which stimulates the contraction at the end of electrical relaxation.
"We have known that calcium signaling is important in regulating the contraction of muscle cells that generate the heartbeat," says Christopher Newton-Cheh, MD, MPH, of the MGH Center for Research human genetics and cardiovascular research center, corresponding and co-lead author of the Nature genetics report. "But finding that calcium is also involved in resetting after each heart beat was a total surprise and represents a new way forward in the cause of arrhythmias."
The Nature Methods article describes a new approach to analyze and map protein networks that stimulate cardiac repolarization - the biological process disrupted in arrhythmias. By integrating the network with the results of the paper Nature Genetics , the researchers were able to identify specific genes involved in the biology of cardiac repolarization, which would have been difficult to achieve from only genetic. This approach has also identified three genetic variants involved in arrhythmias that had been missed in previous studies.
"As people, genes like working in groups, and we have used the new technologies of genomics and proteomics to obtain genes working group involved in the processes that coordinate the beating of the heart and, when malfunctioning, can cause arrhythmias or sudden cardiac death, "says Kasper Lage, PhD, Department of surgery MGH and analytical and translational Genetics Unit, co paper's lead author Nature Methods." potassium signaling is known to being involved in cardiac repolarization, but our network analysis also highlighted a calcium pump and two proteins regulating this pump as guilty. Noting that calcium signaling is also involved in the repolarization was an unexpected and intriguing discovery. "
on Nature Genetics article describes a meta-analysis of genome-wide association studies (GWAS ) involving more than 100,000 people who identified 35 common genes variants pitches - 22 for the first time - associated with alterations in the QT interval identification of a previously unknown role for calcium signaling in the QT interval. is, according to Newton-Cheh, "a quantum leap in our ability to study one of the leading causes of death in people with heart failure - which is known to involve calcium abnormalities -. and a major cause of fatal arrhythmias which occur as a side effect of several drugs "
The team behind Nature Methods paper used quantitative proteomics interaction, which determines not only whether two proteins interact, but the extent of their interaction with the map in mouse hearts networks of proteins encoded by genes known repolarization and confirmed these findings in the eggs of frogs and zebrafish. the integration these results with GWAS analysis revealed that 12 genes in locations identified by the Nature Genetics study proteins encoded in the network described in Nature Methods, providing a strong link between the well-established genes causing rare syndromes and genes of sudden death associated with the change in the QT common in the general population.
"These studies are more than the sum of their parts, because their integration of proteomic networks with genomic results catalyzes the interpretation of genetic results to reveal new biology relevant to dangerous arrhythmias, "said Lage. "We also provide a general methodology to interpret genetic data using proteomic tissue-specific networks. Importantly, our analysis also shows that we are able to use computational algorithms such as the one developed by Elizabeth Rossin, a co- lead author of this paper, interpret functionally large genetic association studies.
"the world of genetics communities now use the tools to Elizabeth," he adds, "and our study follows rigorously and confirms their predictions. This result is important because the revolution in progress in genome sequencing methods and mapping genetic variation produced enormous amounts of genetic data, and we need scalable computing means for interpreting these data sets to guide an overview biological and therapeutic intervention. Our study shows that the predictions made by our calculation tools, supporting their ability to provide insight into the molecular networks affected by genetics in many common complex disorders. "
EmoticonEmoticon