Understanding of mechanism could lead to new drug treatment
A genetic variant linked to sudden cardiac death leads to protein overproduction in heart cells, Johns Hopkins scientists report. Unlike many known disease-linked variants, this one lies not in a gene but in so-called noncoding DNA, a growing focus of disease research.
The discovery, reported in the June 5 issue of The American Journal of Human Genetics, also adds to scientific understanding of the causes of sudden cardiac death and of possible ways to prevent it, the researchers say.
"Traditionally, geneticists have studied gene variants that cause disease by producing an abnormal protein," says Aravinda Chakravarti, Ph.D., a professor of medicine, pediatrics, molecular biology and genetics, and biostatistics in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. "We think there will turn out to be many DNA variants that, like this one, cause disease by making too much or too little of a normal protein."
Chakravarti's interest in sudden cardiac death emerged a decade ago, when it claimed several of his colleagues within a few months. An expert in complex common diseases, he and his team knew that sudden cardiac death can be caused by many conditions. They focused on one: abnormalities in what is known as cardiac repolarization — the time it takes for the heart to gear up to beat again.
The team compared the genetic sequences of tens of thousands of people with their electrocardiogram (ECG) results, identifying several regions on the genome with genetic variations associated with lengthened QT interval, a measure of cardiac repolarization, in the ECG. "The problem is that most of these variants lie outside of genes, in the noncoding DNA that controls how genes are used," Chakravarti says, "so it's hard to tell what genes they're affecting."
Despite the challenge, Chakravarti and his colleagues were able to home in on one suspect region of the genome housing a gene called NOS1AP. "There were many variants grouped in this area," says Ashish Kapoor, Ph.D., a postdoctoral researcher in Chakravarti's laboratory, "so we catalogued all 200 that we found." The team then went through a process of elimination using genetically engineered, lab-grown cells and zebra fish to identify a variant in the noncoding DNA that affected how much protein was made by the nearby NOS1AP gene.
Next, they cultured rat heart cells and engineered them to overproduce NOS1AP. When the concentration of the protein rose in a particular type of heart cell called a cardiomyocyte, the cells' electrical properties changed in a way that is similar to the pattern seen in long QT syndrome.
Kapoor notes that 67 percent of the general population carries the NOS1AP-overproducing genetic variant. "We have observed that NOS1AP genetic variants are associated with sudden cardiac death whether or not they affect a particular person's QT interval, raising the risk by about 40 percent," he says.
Chakravarti notes that the results also add to scientific understanding of how the heart and QT interval work — knowledge with far-reaching implications. For example, many drugs developed for noncardiac conditions have turned out to temporarily lengthen QT interval, a side effect that only turns up after much time and money are spent on drug development. By better understanding regulation of the QT interval, researchers would be better able to predict what types of drugs could affect it.
"Hundreds of genome-wide association studies have been done to find genetic variants associated with disease, but this is one of just a handful of follow-up studies to look for the mechanism behind such a variant," Chakravarti says. "I think we've shown there's great value in asking why."
Link to the article: http://www.cell.com/ajhg/abstract/S0002-9297%2814%2900221-3
Other authors on the paper were Rajesh B. Sekar, Karen Fox-Talbot, Vasyl Pihur, Sumantra Chatterjee, Dan E. Arking, Marc K. Halushka and Gordon F. Tomaselli of the Johns Hopkins University School of Medicine; Nancy F. Hansen, Jim Mullikin and Eric D. Green of the National Human Genome Research Institute; Michael Morley, Jeffrey Brandimarto and Thomas P. Cappola of Perelman School of Medicine at the University of Pennsylvania; Christine S. Moravec of the Cleveland Clinic Foundation; Sara L. Pulit of the University Medical Center Utrecht; Arne Pfeufer of the Helmholtz Zentrum Munchen; Mark Ross and David Bentley of Illumina United Kingdom; Christopher Newton-Cheh of Massachusetts General Hospital; Eric Boerwinkle of the University of Texas Health Science Center; and the QT Interval-International GWAS Consortium.
This work was supported by the National Heart, Lung and Blood Institute (grant numbers RO1 HL086694 and RO1HL105993) and the Donald W. Reynolds Foundation. Affymetrix, Inc. sells products used in the study described in this article. Aravinda Chakravarti was a paid consultant to and member of the Scientific Advisory Board of Affymetrix until December 31, 2013. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Mark Ross and David Bentley are employees of Illumina, Inc., a public company that develops and markets systems for genetic analysis.
Hopkins Scientists ID 10 Genes Associated With a Risk Factor for Sudden Cardiac Death: http://www.hopkinsmedicine.org/news/media/releases/Hopkins_Scientists_ID_10_Genes_Associated_With_a_Risk_Factor_for_Sudden_Cardiac_Death_
New Genes Implicated in High Blood Pressure: http://www.hopkinsmedicine.org/news/media/releases/New_Genes_Implicated_in_High_Blood_Pressure
Scientific Team Sequences 1092 Human Genomes To Determine Standard Range Of Human Genetic Variation: http://m.hopkinsmedicine.org/news/media/releases/1092_human_genomes_sequenced
Shawna Williams | Eurek Alert!
Supercoiled DNA is far more dynamic than the 'Watson-Crick' double helix
13.10.2015 | University of Leeds
New Oregon approach for 'nanohoops' could energize future devices
13.10.2015 | University of Oregon
Physicists of TU Berlin and mathematicians of MATHEON are so successful that even the prestigious journal “Nature Communications” reported on their project.
Security in data transfer is an important issue, and not only since the NSA scandal. Sometimes, however, the need for speed conflicts to a certain degree with...
Having a light touch can make a hefty difference in how well animals and robots move across challenging granular surfaces such as snow, sand and leaf litter. Research reported October 9 in the journal Bioinspiration & Biomimetics shows how the design of appendages – whether legs or wheels – affects the ability of both robots and animals to cross weak and flowing surfaces.
Using an air fluidized bed trackway filled with poppy seeds or glass spheres, researchers at the Georgia Institute of Technology systematically varied the...
Nondestructive material testing (NDT) is a fast and effective way to analyze the quality of a product during the manufacturing process. Because defective materials can lead to malfunctioning finished products, NDT is an essential quality assurance measure, especially in the manufacture of safety-critical components such as automotive B-pillars. NDT examines the quality without damaging the component or modifying the surface of the material. At this year's Blechexpo trade fair in Stuttgart, Fraunhofer IZFP will have an exhibit that demonstrates the nondestructive testing of high-strength automotive body parts using 3MA. The measurement results are available in a matter of seconds.
To minimize vehicle weight and fuel consumption while providing the highest level of crash safety, automotive bodies are reinforced with elements made from...
The MICADO camera, a first light instrument for the European Extremely Large Telescope (E-ELT), has entered a new phase in the project: by agreeing to a Memorandum of Understanding, the partners in Germany, France, the Netherlands, Austria, and Italy, have all confirmed their participation. Following this milestone, the project's transition into its preliminary design phase was approved at a kick-off meeting held in Vienna. Two weeks earlier, on September 18, the consortium and the European Southern Observatory (ESO), which is building the telescope, have signed the corresponding collaboration agreement.
As the first dedicated camera for the E-ELT, MICADO will equip the giant telescope with a capability for diffraction-limited imaging at near-infrared...
Self-driving cars will be on our streets in the foreseeable future. In Graz, research is currently dedicated to an innovative driver assistance system that takes over control if there is a danger of collision. It was nature that inspired Dr Manfred Hartbauer from the Institute of Zoology at the University of Graz: in dangerous traffic situations, migratory locusts react around ten times faster than humans. Working together with an interdisciplinary team, Hartbauer is investigating an affordable collision detector that is equipped with artificial locust eyes and can recognise potential crashes in time, during both day and night.
Inspired by insects
01.10.2015 | Event News
30.09.2015 | Event News
17.09.2015 | Event News
13.10.2015 | Trade Fair News
13.10.2015 | Physics and Astronomy
13.10.2015 | Health and Medicine