Whole-genome study at Johns Hopkins reveals a new gene associated with abnormal heart rhythm

Heart rhythm disturbances are target for preventive treatment.

Using a new genomic strategy that has the power to survey the entire human genome and identify genes with common variants that contribute to complex diseases, researchers at Johns Hopkins, together with scientists from Munich, Germany, and the Framingham Heart Study, U.S.A., have identified a gene that may predispose some people to abnormal heart rhythms that lead to sudden cardiac death, a condition affecting more than 300 thousand Americans each year.

The gene called NOS1AP, not previously flagged by or suspected from more traditional gene-hunting approaches, appears to influence significantly one particular risk factor - the so-called QT interval length - for sudden cardiac death. The work will be published online at Nature Genetics on April 30.

"In addition to finding a genetic variant that could be of clinical value for sudden cardiac death, this study also demonstrates how valuable large-scale genomics studies can be in detecting novel biological targets," says the study's senior author, Aravinda Chakravarti, Ph.D., director of the McKusick-Nathans Institute for Genetic Medicine at Hopkins. "This study, conducted during the early days of a new technology, would have been impossible without the pioneering support of the D.W. Reynolds Foundation in their generous support of our clinical program in sudden cardiac death here at Hopkins."

QT interval measures the period of time it takes the heart to recover from the ventricular beat - when the two bottom chambers of the heart pump. Corresponding to the "lub" part of the "lub-dub" pattern of the heartbeat, an individual's QT interval remains constant. This interval is partly dependent on one's genetic constitution and, moreover, genes also play a role in sudden cardiac death.

"There's a great deal of evidence out there that having a too long or too short QT interval is a risk factor for sudden cardiac death," says the study's co-first author, Dan Arking, Ph.D., an instructor in the McKusick-Nathans Institute. "This makes it appealing to study because it can be measured non-invasively with an EKG, and each person's QT interval, in the absence of a major cardiovascular event, is stable over time, making it a reliable measure."

Identifying those at high risk for sudden cardiac death before fatalities occur has been challenging, both at the clinical and at the genetic level, says the study's other first author, Arne Pfeufer, M.D., of the Institute of Human Genetics at the Technical University in Munich, Germany. Doctors estimate that in more than one third of all cases, sudden cardiac death is the first hint of heart disease. It is widely believed that many factors, genetic and environmental, contribute to irregular heartbeat and other conditions that may lead to sudden cardiac death. Being able to identify predisposed individuals can save their lives by prescribing beta-blockers and other drugs that regulate heart rhythm, and even by implanting automatic defibrillators in those with the highest risk.

In an effort to identify risk factors with a genetic foundation, the researchers took the unconventional approach of starting from scratch and not looking at genes already known or suspected to be involved in heart rhythm.

"Studying individual genes is not going to open new areas of research," says Chakravarti. "Using a whole-genome approach allows us to find new targets that we never would have imagined."

So instead of focusing on so-called candidate genes with known functions that are highly suspect in heart beat rhythm, the team first focused on people who have extremely long or short QT intervals. The researchers used subjects from two population-based studies, about 1800 American adults of European ancestry from the Framingham Heart Study of Framingham, Mass., and about 6,700 German adults from the KORA-gen study of Augsburg, Germany.

The research team then searched for any specific DNA sequences that showed up more frequently in people who have longer or shorter QT intervals than in those with normal QT intervals. To do this, they examined the DNA sequences of both long and short QT people. The human genome contains 3 billion letters, known as nucleotides. Each person's genome differs from the next person's by as many as 10 million nucleotides. The researchers looked for single nucleotide variations - known as single nucleotide polymorphisms, or SNPs for short - that track with having a long or short QT interval.

Only one particular SNP correlated with QT interval. That SNP was found near the NOS1AP gene, which has been studied for its function in nerve cells and was not previously suspected to play a role in heart function. However, the research team found that the NOS1AP gene is turned on in the left ventricle of the human heart. And the "lub" part of the "lub-dub" heartbeat corresponds to ventricular contraction. So NOS1AP is active in the right place and time to play a role in QT interval.

Further studies revealed that approximately 60 percent of people of European descent may carry at least one copy of this SNP in the NOS1AP gene. According to the researchers, this particular SNP is responsible for up to 1.5 percent of the difference in QT interval, meaning that other genes, missed in this study, certainly contribute to QT length.

Now that researchers know that variants of the NOS1AP gene correlate with QT interval length, they hope to figure out exactly how the DNA sequence variations alter the function of the gene, and how changes in gene function affects heart rhythm.

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The Hopkins researchers were funded chiefly by the D.W. Reynolds Clinical Cardiovascular Research Center, which focuses on sudden cardiac death. Additional support was provided by the Johns Hopkins University, the National Institutes of Health, a GlaxoSmithKline Competitive Grants Award Program for Young Investigators, an unrestricted grant from Pfizer Inc., and the German Federal Ministry of Education and Research in the context of the German National Genome Research Network (NGFN). The Framingham Heart Study is supported by the National Heart, Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine and the Cardiogenomics Program for Genomic Applications.

Authors on the paper are Arking, Wendy Post, Linda Kao, Morna Ikeda, Kristen West, Carl Kashuk, Eduardo Marbán, Peter Spooner, and Chakravarti, all of Johns Hopkins; Pfeufer, Mahmut Akyol, Siegfried Perz, Shapour Jalilzadeh, Thomas Illig, Christian Gieger, Erich Wichmann, and Thomas Meitinger of the GSF National Research Center of Environment and Health in Neuherberg, Germany; Christopher Newton-Cheh, Chao-Yu Guo, Martin Larson, and Christopher O'Donnell of the National Heart, Lung and Blood Institute's Framingham Heart Study; Joel Hirschhorn of Harvard Medical School, and Stefan Kaab of Ludwig-Maximilians University of Munich.

On the Web:
http://www.nature.com/ng/index.html
http://www.hopkinsmedicine.org/geneticmedicine/index.html


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