When the aorta, the major artery arising from the heart, becomes enlarged and weakened, the condition (called a thoracic aortic aneurysm) is life threatening. The situation becomes acute when wall of the aorta begins to tear (a dissection) or ruptures.

Understanding the genetic component of this dangerous disorder might help doctors identify people at risk and treat them before the weakened artery endangers their lives. In a recent study, researchers at Baylor College of Medicine and The University of Texas Health Science Center at Houston (UT Health) found 47 regions of the genome where portions of genetic material were deleted or duplicated, which can affect genes and the proteins they produce. These are called copy number variations.

New paradigm of mutations

"For a long time, we concentrated on single mutations that would, by themselves, cause disease," said Dr. Siddharth Prakash, assistant professor of molecular and human genetics at BCM and first author of a report that appears online today in the American Journal of Human Genetics. "Now we have come up with a new paradigm where we see different types of mutations – rare mutations. Instead of one gene, dozens of genes may be involved in the disease and each gene variant may account for a few cases. Together, they affect a common biological mechanism that causes the disease.

"As a class of defects, they may be as great or greater a cause of disease than the single gene defects," he said. "In these variants, there may be only one copy of a gene instead of the normal two. Or there may be three copies. That could result in more or less of a protein or it could disrupt production of a protein. This can be passed from generation to generation."

Dr. John W. Belmont, professor molecular and human genetics at BCM, and Dr. Dianna M. Milewicz, professor of medicine at UT Health, are senior authors of the report. Prakash spoke about the findings at the recent American Heart Association Scientific Sessions in Chicago.

Genome-wide analysis

In this study, Prakash and his colleagues from BCM and UT Health did a genome-wide analysis of thoracic aortic aneurysms and dissections in 418 patients. They identified 47 copy number variant regions that were unique to patients with these aneurysms. Closer scrutiny of the genes involved in the copy number variants showed that they regulate smooth muscle adhesion or ability to contract. They also interact with smooth muscle specific form of alpha-actin and beta-myosin, both proteins important in muscle formation and activity. When altered, they are known to cause familial from of thoracic aortic aneurysms and dissections.

A comparison of patients with familial forms of the aneurysm disorder to patients with sporadic forms showed that those with the familial forms had more copy number variations. However, the research shows that rare copy number variations that disrupt smooth muscle adhesion or contraction contribute to both forms of the disorder.

Cellular pathways

Looking for copy number variants that affect cellular pathways may provide answers not found in genome-wide association studies, said Prakash.

"A pathway is a biological process governed by a set of gene that work together to accomplish a single purpose such as growing the cell larger, cell movement or cell adhesion," he said. "Considering the pathway allows us to make sense of disparate hits across the genome. If these variants target a common mechanism, then you should target that pathway rather than an individual gene."

In some cases, a single gene may be the master regulator of a pathway and, thus, make the ideal target, he said. Using gene chips or microarrays, physicians could evaluate pathways and identify aneurysms in those people who have variants in the appropriate pathway.

These aneurysms are usually without symptoms until they rupture or begin to tear.

"If we could find a way to catch the problem before a dissection or rupture, we could make a profound difference in a disorder that kills more than 8,000 people each year in the United States," said Prakash.

Others who took part in this work include Drs. Scott A. LeMaire, Ludivine Russell, Joseph S. Coselli, Molly S. Bray and Suzanne M. Leal, all of BCM and Drs. Dongchuan Guo, Ellen S. Regalado, Hossein Golabbakhsh, Ralph J. Johnson, Hazim J. Safi, Anthony L. Estrera and Dianna M. Milewicz of UT Health.

Funding for this work came from the National Institutes of Health, the Vivian L. Smith Foundation, the TexGen Foundation, the Doris Duke Foundation and the Thoracic Surgery Foundation for Research and Education.