Although genome-wide association studies have linked DNA variants in the gene SCN10A with increased risk for cardiac arrhythmia, efforts to determine the gene's direct influence on the heart's electrical activity have been unproductive.
Now, scientists from the University of Chicago have discovered that these SCN10A variants regulate the function of a different gene, SCN5A, which appears to be the primary gene responsible for cardiac arrhythmia risk. The SCN10A gene itself plays only a minimal role in the heart, according to the study, published in the Journal of Clinical Investigation on March 18.
"Significant effort has been invested into understanding the function of SCN10A in cardiac rhythm control, with underwhelming results," said study co-leader Ivan Moskowitz MD, PhD, associate professor of pediatrics, pathology and human genetics at the University of Chicago. "It turns out that the genetic variation within SCN10A that confers arrhythmia risk actually functions on a different gene. This study highlights the fact that DNA variation associated with disease can have regulatory impact on functional targets located a considerable distance away."
Mutations within the SCN10A gene are linked with increased risk of Brugada Syndrome, which causes cardiac arrhythmias and is a leading cause of death amongst youth in some parts of the world. Genome-wide association studies—large scale experiments that look for genetic variants across the human genome with statistical associations to certain traits or diseases—were used to identify these variants, but follow-up studies have been unable to determine their function.
Curious about previous ambiguous results, Moskowitz and his colleagues looked for other genes with links to SCN10A. First, they discovered that the region of SCN10A that conferred arrhythmia risk physically contacted a neighboring gene—SCN5A—which is well-known to have an important role in cardiac arrhythmias and sudden cardiac death. They then showed that these contacts are functional, and that by removing the implicated sequences from SCN10A, expression of SCN5A was profoundly diminished.
When they analyzed large-scale human data, the team found that the SCN10A variant originally identified for Brugada Syndrome risk was associated with lowered levels of SCN5A. But the variant had no detectable effect on the levels of SCN10A.
Taken together, the evidence suggests that any link between SCN10A and cardiac arrhythmia is due to its connection with SCN5A expression. Through the results of this study, Moskowitz believes scientists will now focus on the correct gene, SCN5A, to better understand genetic risk for cardiac arrhythmia and hopes this will lead to more accurate diagnostics and potential therapies in the future.
This study also illustrates how highly-publicized genome-wide association studies can be misleading for researchers. Study co-leader Marcelo Nobrega, PhD, an associate professor of human genetics at the University of Chicago, published a similar finding for a gene associated with obesity, on March 12th in Nature.
"Genome-wide association studies have been very successful in implicating genetic variation associated with a host of human diseases and traits," Moskowitz said. "However cases like this study demonstrate that we must be more careful to evaluate the functional target of genome-wide association study hits, before we jump to conclusions that can have costly implications for how we investigate human health and generate disease diagnostics and therapies."
The study, "A common genetic variant within SCN10A modulates cardiac SCN5A expression," was funded by the National Institutes of Health, the European Community's Seventh Framework Programme contract, the Cardiovascular Onderzoek Nederland, the German Foundation for Heart Research and the Federal Ministry of Education and Research. Additional authors include Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E. Arnolds, Harmen J.G. van de Werken, Petra Klous, David McKean, Jochen D. Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H. Yang, Tamara T. Koopmann, Michiel E. Adriaens, Connie R. Bezzina, Wouter de Laat, Christine Seidman, J.G. Seidman, Vincent M. Christoffels and Phil Barnett.
Kevin Jiang | EurekAlert!
New switch decides between genome repair and death of cells
27.09.2016 | University of Cologne - Universität zu Köln
A blue stoplight to prevent runaway photosynthesis
27.09.2016 | National Institute for Basic Biology
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...
Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.
Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.
Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...
28.09.2016 | Event News
27.09.2016 | Event News
23.09.2016 | Event News
28.09.2016 | Medical Engineering
28.09.2016 | Materials Sciences
28.09.2016 | Business and Finance