Researchers Find First Heart Attack Gene
CLEVELAND, Nov. 27 /PRNewswire/ -- Scientists at The Cleveland Clinic have identified the first gene confirmed as a cause of coronary heart disease in humans. Results of this groundbreaking research will appear in the Nov. 28 issue of Science.
The gene, MEF2A, was discovered by methodically studying the genetic makeup of 21 members of an Iowa family plagued for generations by incidents of coronary artery disease and heart attack. (Research with the family has continued beyond preparation of the Science article. Of the more than 50 family members who have provided DNA, the genomes of 26 family members now have been analyzed.)
"What we discovered is a deletion mutation," said Eric J. Topol, M.D., chairman of the Department of Cardiovascular Medicine at The Cleveland Clinic. "The elements missing from this gene represent 21 base pairs of nucleotides and seven amino acids. This deletion affects coronary artery walls, making them less able to protect themselves from plaque buildup and heart disease." (Hear Dr. Topol's comments: http://www.prnewswire.com/broadcast/Topol\Topolpage.html )
Dr. Topol, who also serves as the Clinic's provost and chief academic officer, said it is unlikely that many other families will be found with the exact same genetic mutation. Instead, researchers will seek to pinpoint smaller mutations involving the same gene that may contribute less dramatically to the development of heart disease.
"People with this exact MEF2A mutation have essentially a 100-percent chance of having a heart attack or developing coronary artery disease," Dr. Topol said. "For them, it's not a matter of 'if,' it is a matter of 'when.' For that reason, we think this specific mutation will prove to be rare. Most genes that will be discovered to induce heart attack will be more common and not carry as high a risk."
No matter what the future of heart disease research holds, Dr. Topol said, one message remains clear: "Lifestyle choices are vitally important in the fight against heart disease. For people with this deletion mutation, their battle is to identify and control lifestyle factors -- weight, blood pressure, diet -- to delay the onset of heart disease as long as possible. For people without a genetic predisposition, they must make it their responsibility to take care of themselves to prevent heart disease from developing."
Every patient in the Iowa family who experienced a heart attack had at least one coronary risk factor. As Cleveland Clinic scientists looked for the genetic link, researchers in the laboratory of Qing Wang, Ph.D., scanned the complete genomes of all participating members of the family.
The area of interest proved to be located on chromosome 15, long arm 26. This region contains about 93 genes. Dr. Wang and his colleagues noticed a big difference in the MEF2A gene between family members who had developed coronary heart disease and those who had not.
"I was quite surprised to find such a large deletion mutation," said Dr. Wang, director of the Clinic's Center for Cardiovascular Genetics. "I couldn't quite believe it at first. But once we verified this, the real work began to try to determine exactly why the mutation mattered."
The MEF2A gene makes a regulatory protein that controls the expression of hundreds or even thousands of other genes in the endothelium, the barrier between blood vessels and blood elements. Cleveland Clinic scientists suspect the resulting genetic changes weaken the endothelium, making it more susceptible to invasions and attacks by monocytes and macrophages, which allow the formation of atherosclerotic plaques. Once the arterial wall integrity is lost and thrombosis has occurred, unstable angina, heart attack or sudden cardiac death can result.
"Finding the gene opens a new avenue through which scientists can track the pathway that leads to coronary heart disease and heart attack," Dr. Wang said. "Genes in that pathway then can be used as targets to design new drugs intended to prevent or treat heart disease. Finding the gene also will make it easier to definitively diagnose patients with highly significant family histories of heart disease."
Future research will focus on pinpointing the roles of the missing nucleotide pairs and amino acids, as well as searching for ways to counteract the negative impact on artery walls. This research is among the most exciting ever undertaken by The Cleveland Clinic, Dr. Topol said, because of its potential to benefit so many people.
"Despite all medical advances to date, heart disease remains the No. 1 killer in the developed world," he said. "Someone suffers a coronary event every 29 seconds, and someone dies every minute. Unlocking the genetic secrets of this disease is a first step in a new research avenue to help save countless lives."
Other researchers who worked on the MEF2A project include postdoctoral fellows Lejin Wang and Chun Fan, and cardiology study coordinator Sarah Topol, all of The Cleveland Clinic.
The Cleveland Clinic Foundation, located in Cleveland, Ohio, is a not-for- profit multispecialty academic medical center that integrates clinical and hospital care with research and education. The Cleveland Clinic was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. U.S. News & World Report consistently names The Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. In 2003, The Cleveland Clinic is ranked fifth overall. Approximately 1,200 full-time salaried physicians at The Cleveland Clinic and Cleveland Clinic Florida represent more than 100 medical specialties and subspecialties. In 2002, there were nearly 2.5 million outpatient visits to The Cleveland Clinic and more than 52,000 hospital admissions. Patients came for treatment from every state and from more than 90 countries. The Cleveland Clinic website address is http://www.clevelandclinic.org/ .
Patients seeking more information about this study are asked to call 800/223-2273 or log on to http://www.clevelandclinic.org/heartcenter .
The Cleveland Clinic FoundationCONTACT: Alicia Sokol, +1-216-445-9661, or Angela Calman,+1-216-445-1546, both of The Cleveland Clinic Foundation
Web site: http://www.clevelandclinic.org/