October 20, 2004
New Clinic Research Advances Efforts to Understand Genetics of Heart Disease
In November 2003, Cleveland Clinic researchers announced the discovery of the first gene confirmed as a cause of coronary heart disease in humans. Less than a year later, their studies indicate this "heart attack gene" is more prevalent among Americans than expected.
According to their findings, as many as 1 percent to 2 percent of all U.S. heart attack and coronary artery disease patients may carry mutations of the MEF2A gene. Cleveland Clinic researchers discovered this gene by methodically studying the genetic makeup of 21 members of an Iowa family plagued for generations by clogged arteries and heart attacks.
When researchers initially discovered an MEF2A deletion mutation in the Iowa family, they acknowledged it was unlikely that the exact genetic mutation would be found in other people. Instead, they began to search for smaller mutations involving the same gene, and they found just that.
The latest mutation involves three novel mutations in exon 7, rather than exon 11 as in the original MEF2A mutation. The new mutations also involve one base pair point change, instead of a 21 base pair deletion. The full study is being posted online today in the journal Human Molecular Genetics.
"This is another exciting and vital piece in the heart-disease puzzle," said Eric J. Topol, M.D., chairman of the Department of Cardiovascular Medicine at The Cleveland Clinic. "This study indicates that coronary artery disease and heart attack can result from a spectrum of MEF2A mutations. This work along with that of other groups will quickly solve the genetic bar code for coronary disease, greatly enhancing our efforts to prevent it or make an early diagnosis."
Dr. Topol, who also serves as the Clinic's provost and chief academic officer, said the study indicates that a significant number 1.93 percent of the population suffering from coronary artery disease or heart attack may carry MEF2A mutations.
The MEF2A gene makes a 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 drive inflammation in the artery wall. These attacks allow atherosclerotic plaques to form. Once the integrity of the arterial wall is lost and blockages have occurred, unstable angina, heart attack or sudden cardiac death can result.
For the latest study, researchers reviewed the genetic data of 207 patients with coronary artery disease/heart attack and 191 patients with normal angiograms as a control group. No MEF2A mutations were detected in the control group, however three novel mutations were identified in four of the 207 coronary artery disease/heart attack patients (1.93 percent).
Researchers concluded the gene carriers with loss-of-function mutations appear to be associated with less severe coronary artery disease and did not develop heart attack, as did the Iowa family with a more severe mutation. This supports the theory that a range of mutations is likely and that a range of corresponding outcomes exists. Further study will be needed to define the actual prevalence of MEF2A mutations.
"Identifying new mutations in the MEF2A gene is a significant finding because it brings us one step closer to unlocking the genetics behind heart disease and heart attack," said Qing Wang, Ph.D., director of The Cleveland Clinic's Center for Cardiovascular Genetics. "The finding that 1 percent to 2 percent of the heart disease population have mutations in MEF2A also is significant because it brings us closer to the development of a future genetic testing kit for these patients. Aggressive lifestyle modifications and preventive therapies will help patients to prevent or delay the onset of heart attacks."
The study was conducted in Dr. Wang's laboratory. Other researchers who worked on this project include M.R. Krishna Bhagavatula, Chun Fan, Gong-Qing Shen, June Cassano and Edward Plow, 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. Approximately 1,200 full-time salaried physicians at The Cleveland Clinic and Cleveland Clinic Florida represent more than 100 medical specialties and subspecialties. In 2003, patients came for treatment from every state and from nearly 90 countries. The Cleveland Clinic website address is www.clevelandclinic.org .
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The Cleveland Clinic 2004
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