Genes causing sudden heart failure discovered
Scientists have found the genes behind the hereditary heart disease long QT syndrome that leads to sudden heart failure -- even in young people.
In recent years, the media have reported about several cases of young highly trained athletes suddenly dropping dead on the field.
They were all struck by sudden heart failure.
One of the causes of sudden heart failure is the hereditary condition long QT Syndrome that causes the intervals between the heart’s contraction and beat to be longer than normal. In some cases this can cause the heart to stop suddenly and without warning.
A team of scientists have now identified which genes control the length of the interval and this is the first step towards a treatment for people who suffers from long QT interval.
Long QT Syndrome is a disease that can lead to cardiac fibrillation and cardiac arrest.
Symptoms of long QT syndrome often start early in life with instances of fainting and near fainting. The first symptom can also be death.
People diagnosed with long QT syndrome can be treated with beta-blockers or an implanted advanced pacemaker that can kick-start the heart if it stops beating.
Their findings were recently published as two studies: one about the genes behind the QT interval in Nature Genetics, and one in Nature Methods about a new method for identifying genes behind diseases.
One step closer to treating long QT interval Syndrome
The combination of the two new studies brings scientists closer to understanding changes in the QT interval.
“Before doctors can treat patients suffering from a prolonged QT interval, they must first find the proteins that aren’t working properly,” says co-author Alicia Lundby, postdoc at Novo Nordisk Foundation for Protein Research at the University of Copenhagen. “With these studies we are now a step closer to doing that.”
New method has great potential, according to researchers
According to Professor Jesper Velgaard Olsen of the Novo Nordisk Foundation Center for Protein Research the new method of analysis will revolutionise major genetic studies in future:
When the heart beats, an electric impulse above the heart muscle makes the heart contract. The same electric current also makes the heart relax again.
If there are problems with these currents, it means the patient has heart problems.
Researchers have yet to find the molecular reasons why some hearts take longer to relax after a heartbeat than others.
Professionals use an electrocardiogram (EKG) to measure the heartbeat and the current above the heart.
“The potential of the new method we have developed is enormous,” he says. “It’s a general method that can be used to identify disease genes in major genetic studies in future. Specific identification of disease genes is very important to the future medical applications of the studies.”
Dean Allan Flyvbjerg of the Faculty of Health Sciences at Aarhus University has not taken part in the new studies, but he has read about them. According to him the method study is interesting.
“With their new method, the researchers have managed to connect the findings of a major genetic study to functionality and potential clinical application. It is by far the most interesting of the two studies, and that’s very well done,” says Flyvbjerg.
Heart rhythms of 100,000 people measured
In the Nature Genetics study the researchers have employed EKG (the beeping machine that measures people’s heart rhythms in the hospital) to measure the heart rhythms of more than 100,000 people.
Scientists can use the results of the EKG measurements to determine the length of the QT interval (see image).
The length of the QT interval should preferably be between 0.36 and 0.44 seconds while anything above 0.44 seconds is considered an extended QT interval.
After the EKG measurements the researchers analysed the participants’ DNA and found variations in the DNA that could be related to the changes in the QT interval.
However, even though the researchers could identify which regions of the genome that were responsible for the length of the QT interval, they weren’t able to determine which genes caused the problem. This is because the different regions contained many different genes.
The problem, which is typical for major genetic studies, led to an even bigger study (published in Nature Methods) of which Lundby is the primary author.
Next step: what happened to the genes?
In the Nature Methods study the researchers developed a technical and analytical method of identifying which genes in a region of DNA can be related directly to the length of the QT interval.
However, even though the researchers have identified the implicated genes, they haven’t found out what is wrong with the genes when the QT interval is extended.
“That’s the next step. What we’ve done so far is identify the relevant genes,” says Lundby.
In order to validate that the genes really do have influence on the length of the QT interval, the researchers created some genetically manipulated zebra fish without the genes in question.
The heart rhythms of the zebra fish and the QT interval confirmed that the researchers had found the right genes.
The method is both technical and analytical
In the development of the new Danish method of analysis for major genetic studies Alicia Lundby and her colleagues have examined which proteins are located near the proteins known have an influence on QT interval length.
The proteins in question are the various membrane proteins that transport ions across the cell membrane.
This part of the work is based on advanced mass spectrometry-technology (a technology for identifying large molecules from their weight), and according to Lundby, she and her colleagues at the Novo Nordisk Foundation Center for Protein Research are very good at that.
“We know that the function of the membrane proteins that transport ions across the cell membrane are influenced by other proteins within close proximity. Because we know some very specific membrane proteins that influence the QT interval, we examined what other proteins that are connected to the ion transporters,” says Lundby.
Armed with the new data, the researchers could compare the results of the protein analysis with the results of the genetic study, in order to find out which genes in the identified regions code for a protein in a network with an ion transporter.
“In that way, we could compare the two studies and find out which genes influence the QT interval,” says Lundby.
Analysis tool could be used in other studies
Lundby also says that the new analysis tool will play a very important part in some of the major genetic studies in future.
The analysis tool will make it easier for researchers to find specific genes with an influence on a specific disease in large so-called GWAS studies (Gene-Wide Association Studies), where researchers examine hundreds of thousands of people, looking for genetic differences that could explain the disease.
“We are very excited that the development of this method of analysis was a success,” says Lundby.
Calcium recently revealed as key player in development of long QT interval
Even though the researchers behind the new studies have taken a big step in the direction of a better understanding of the genetics behind the length of the QT interval, Lundby realises that it could be a long while before the results of the genetic study can benefit treatment.
However, the studies also brought another result that could pave the way for treatment sooner.
The researchers discovered that the implicated genes make proteins that transport calcium in the cells of the heart.
Thus the study shows that calcium is very important to the length of the QT interval.
“Perhaps it would be possible to find a way to use this knowledge to make medication that influences calcium transport. It could pave the way for medication sooner than if we have to examine the functions of the individual genes in the heart first,” says Lundby.
Translated by: Iben Gøtzsche Thiele
- Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization,Nature Genetics, doi:10.1038/ng.3014
- Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics, Nature Methods, doi:10.1038/nmeth.2997