Further study of this master switch -- a gene called GATA2 -- and the genes it controls may uncover a regulatory network that influences whether a person inherits coronary artery disease, the most common form of heart disease in the Western world, according to the researchers. The discovery also may lead to development of genetic tests to predict an individual's risk of developing coronary artery disease, the scientists said.
"We hope that one day it will be possible to use these gene variations to predict who is susceptible to cardiovascular disease," said Jessica J. Connelly, a postdoctoral fellow at the Duke Center for Human Genetics and lead author on the study. "This finding is the first step before we can develop such a test for use in patients."
People who know they are at higher risk may be encouraged to take early steps to modify behaviors, such as smoking or consuming foods high in saturated fats, that are known to play a role in promoting heart disease, the scientists said.
The team reports its findings in the August 2006 issue of Public Library of Science (PLoS) Genetics. The research was sponsored by the National Institutes of Health.
Coronary artery disease affects more than 13 million Americans and is one of the nation's leading causes of death. The disease occurs when the arteries supplying blood to the heart become narrowed or clogged by plaque deposits. Left untreated, the disease can completely block the blood flow to the heart, leading to a heart attack.
Coronary artery disease is what scientists call a "complex" genetic disease – that is, it results from the accumulation of a number of small genetic changes that influence an individual's ability to cope with environmental and biological effects. While risk factors such as smoking, high blood pressure and high cholesterol are known to contribute to coronary artery disease, little is known about genes that render an individual susceptible to developing the disease, according to the Duke researchers.
"It is extremely difficult to pin down genes associated with a complex disease such as heart disease," said Simon G. Gregory, Ph.D., assistant professor of medicine at the Duke Center for Human Genetics and senior investigator on the study.
Two pieces of evidence pointed the researchers' attention to GATA2 as a likely candidate, Gregory said.
In a previous study, the researchers had scanned the entire genome -- the body's genetic blueprint -- of a group of families with at least two siblings with early onset coronary artery disease, looking for regions of "linkage" where DNA variations appeared to be inherited along with the disease. They found just such a region: a small section of the long arm of chromosome 3 where GATA2 is located. Chromosome 3 is one of the 23 pairs of chromosomes that comprise the human genome.
In a separate study led by David Seo, M.D., assistant professor of medicine, another group of Duke researchers found that GATA2 was turned on, or expressed, differently in diseased areas of aorta, the primary artery supplying the heart, in people with damaged hearts. This finding suggested that the gene could be involved in susceptibility to coronary artery disease, the researcher said.
In the current study, the researchers focused on specific gene variants, called single nucleotide polymorphisms (SNPs), which occur when a single nucleotide building block in the long strand of DNA is altered. The researchers sought SNPs that occurred more or less often in individuals with coronary artery disease than in individuals without it, as such a link would indicate that these gene variants were associated with the disease.
The researchers obtained DNA from 3,000 individuals from 1,000 families affected by coronary artery disease, through a collaborative study, called GENECARD, led by William E. Kraus, M.D., associate professor of medicine, under way at the Duke Center for Human Genetics. Using these DNA samples, the researchers scanned the GATA2 gene for SNPs that differed in sequence between individuals with and without coronary heart disease.
"We identified five SNPs that were significantly associated with early onset coronary artery disease," Gregory said.
The researchers then looked for the same SNPs in a separate group of 600 patients with early onset coronary artery disease who had volunteered to be studied while being examined at the cardiac catheterization laboratories at Duke University Hospital. The team identified significant association of two of the same SNPs in this independent group of patients. This finding, according to the researchers, validated the suspected link between GATA2 and coronary artery disease.
"A huge strength of our study is that we used two separate populations, finding the association between GATA2 and coronary artery disease in one population and then validating the finding in another," Connelly said.
GATA2 is a transcription factor, a master switch that controls when and where other genes are expressed. According the researchers, the SNPs identified in this study may change the ability of this transcription factor to influence the activity of many other genes, demonstrating how small genetic changes can influence multiple genetic outcomes.
The researchers said they now can use molecular techniques to look at where GATA2 acts within the genome to see what other genes also contribute to cause cardiovascular disease.
"As science progresses in this field, we are compiling a portfolio of genes that contribute to cardiovascular disease," Gregory said.
The hope, according to the Duke team, is that this discovery will be followed by others that eventually will enable scientists to identify people who are predisposed to developing coronary artery disease long before they develop any symptoms of the disease.
"What we have found is that changes in GATA2 affect susceptibility to developing coronary artery disease," Connelly said. "Eventually, we hope to create a diagnostic test containing all the genes affected in cardiovascular disease and use it to identify which SNPs are present in an individual. This approach will enable us to generate a profile of risk for developing cardiovascular disease."
The profile would not say conclusively whether or not a person would develop coronary heart disease, but could tell individuals whether they are more or less at risk for developing the disease, Gregory said.
Marla Vacek Broadfoot | EurekAlert!
Atomic-level motion may drive bacteria's ability to evade immune system defenses
24.04.2017 | Indiana University
Two-dimensional melting of hard spheres experimentally unravelled after 60 years
24.04.2017 | University of Oxford
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
24.04.2017 | Physics and Astronomy
24.04.2017 | Materials Sciences
24.04.2017 | Life Sciences