New Genetic Research Could be Key to Uncovering a Deadly Form of Heart Disease

3/5/2008

The devastating heart condition known as left main coronary artery disease is the worst form of heart disease and develops silently.  Victims often experience no symptoms before sudden death.   But new genetic research led by scientists at the University of Miami Miller School of Medicine and Duke University could lead to a simple blood test to detect the abnormality in those people most at risk.

“Now that we have discovered a genetic link to the gravest heart disease in the world, we may be able to target more specifically patients who truly need expensive and extensive testing," said Pascal J. Goldschmidt, M.D., senior vice president for medical affairs and dean of the Miller School, and one of the authors of a study just published online in the Annals of Human Genetics.  "Just a simple blood test for the genetic marker could be enough to identify individuals who are more susceptible to developing the condition."

Researchers have long known that coronary artery disease has a strong genetic component, and that is why family history is considered such a significant risk factor.  Previous studies by the same research group identified a large region of chromosome 3 as containing genes important to developing coronary artery disease.  This time around a portion of that group, led by Goldschmidt and Jeffery M Vance, M.D., Ph.D., chairman of the new Dr. John T. Macdonald Foundation Department of Human Genetics and Genomic Medicine at UM, along with first author Liyong Wang, Ph.D., from the Miami Institute for Human Genomics at UM,   identified the limbic system-associated membrane protein (LSAMP) as a key gene for left main disease.  LSAMP  was just discovered and known to be a tumor suppressor gene and important to brain development.

The gene had never before been linked to coronary artery disease, but in the current association study of individuals with left main disease, the researchers saw significant evidence of an association with this gene.   The association was also confirmed when families with at least two siblings diagnosed with early-onset coronary artery disease were studied. “Through finemapping we were able to identify a specific area of the gene, known as the risk haplotype, that was highly associated with left main coronary artery disease, and accounted for a substantial fraction of the risk for the disease in our population of patients,” Goldschmidt said.

The researchers also found evidence while studying gene expression pattern in human aortas that LSAMP is related to the formation of atherosclerotic plaques in arteries, which is a primary cause of heart disease such as left main disease.  During the analysis the researchers were able to determine that the risk haplotype is associated with altered LSAMP expression, which leads to the enhanced proliferation of smooth muscle cells.  It is these same cells that lead to the formation of plaques in the inner lining of the arteries which results in left main disease.

“This is the beauty of doing genetic research today – the techniques allow us to find tools that will save the life of so many of our patients and citizens,” Goldschmidt said.  “Now we not only have identified a risk haplotype in the LSAMP gene associated with left main disease, but we’ve also linked it to what physically happens inside the walls of the arteries when this gene is at work.”

“The beauty of coronary artery disease such as left main disease is that so much can be done to suppress and prevent the dreadful consequences of this condition.  It is estimated that we  prevent in excess of 800,000 deaths per year in the United States as a result of our work over the past 50 years.  But of course, the greatest challenge is to find out who is at the highest risk.  The LSAMP gene halpotype is of formidable help in doing just that, identifying people at risk!”

David Seo, M.D., associate professor of medicine at the Miller School, and Margaret Pericak-Vance, Ph.D., director of the Miami Institute for Human Genomics, and the Dr. John T. Macdonald Foundation Professor of Human Genomics, were also authors on the paper.  The study was funded by a $14 million NIH grant from the National Heart, Lung and Blood Institute.