Common genetic variants increase risk of aortic dissection

Dianna Milewicz, M.D., Ph.D. director of the John Ritter Research Program, and her team of researchers at UTHealth, along with researchers at Baylor College of Medicine, published the discovery of common genetic variants which predispose individuals to thoracic aortic aneurysms and dissection (TAAD) in the absence of a family history of the disease (called sporadic TAAD) or a genetic syndrome which causes TAAD.  The variants are located in the same region on chromosome 15 as the FBN1 gene; changes (mutations) in FBN1 cause Marfan syndrome.  The researchers hope an increased understanding of how mutations and variants in FBN1 lead to thoracic aortic disease will ultimately result in effective treatments for individuals with sporadic TAAD.

HOUSTON – (Sept. 12, 2011) – Richard Holbrooke, John Ritter, Lucille Ball, Jonathan Larson and Great Britain’s King George II were all taken by the same silent killer: an acute aortic dissection.

Now, scientists led by researchers at The University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine (BCM) have found an association with a common genetic variant in the population that predisposes people to acute dissections and can approximately double a person’s chances of having the disease.

An aortic aneurysm is an enlargement or ballooning of the aorta in the segment where it comes out of the heart (thoracic aortic aneurysm). The natural history of a thoracic aortic aneurysm is to enlarge without symptoms over time, leading to instability of the aorta and ultimately an acute aortic dissection. The dissection is a tear in the aorta that allows blood to flow within its layers. It is a life-threatening event, with up to 40 percent of patients dying suddenly.

Although the average age of a person who suffers an aortic dissection is early 60s, the disease can strike at any age. Since the majority of individuals have an aortic aneurysm prior to dissection, identification of these aneurysms is critical since the aneurysm can be surgically repaired to prevent the aortic dissection, which typically occurs when the diameter of the aneurysm reaches twice that of the normal aorta. Therefore it is important to know who is at risk for this disorder.

The results of the research were published in the Sept. 11, 2011 advance online issue of Nature Genetics. Senior author is Dianna M. Milewicz, M.D., Ph.D., professor and the President George H.W. Bush Chair in Cardiovascular Research at The University of Texas Medical School at Houston, part of UTHealth. 

“This is the first time we’ve found an association with a common genetic variant in the population that predisposes people to thoracic aortic aneurysms that cause acute aortic dissections. This variant in the DNA is on chromosome 15 (15q21.1) and involves a gene called FBN1. We already know that mutations in this gene cause Marfan syndrome, which is a genetic syndrome that strongly predisposes individuals to aortic dissections but also causes people to grow tall and have weak eyes,” said Milewicz, who is also director of the Division of Medical Genetics at the UTHealth Medical School and heads the UTHealth John Ritter Research Program in Aortic and Vascular Diseases. “Although patients with aortic dissection in our study did not have Marfan syndrome, this study suggests that the same pathways are involved in causing aortic dissections in patients with and without Marfan syndrome.” 

Milewicz said the research has implications for using drugs to treat patients to prevent aortic aneurysms from even forming, such as losartan, which is now being tested in clinical trials for people with Marfan syndrome. “Whether they have Marfan or the common variant in FBN1, it may be the same pathway and we may be able to treat these patients the same way. That means that what we learn in treating patients with Marfan syndrome has implications for this larger group of individuals with thoracic aortic disease,” she said.

“Over the past two decades, there has been remarkable progress in understanding the causes of aortic aneurysms and dissections in patients with inherited disorders, particularly Marfan syndrome. However, up to 80 percent of patients with thoracic aortic aneurysms and dissections do not have a known inherited cause, and the genetic factors that impact susceptibility to aortic disease in these patients are poorly understood,” said the study’s first author Scott A. LeMaire, M.D., professor of surgery and director of research in the Division of Cardiothoracic Surgery at BCM and surgeon at the Texas Heart Institute at St. Luke’s Episcopal Hospital. “This gap in our understanding of ‘sporadic’ disease motivated us to conduct this study, which would not have been possible without the tremendous efforts of a large team of dedicated collaborators.”

The study examined more than 1,300 patients who had sporadic thoracic aortic disease, meaning they did not have a known family genetic history or genetic syndrome associated with the disease. The patients came from the Memorial Hermann Heart & Vascular Institute, the Texas Heart Institute and Harvard Medical School, as well as from the National Institutes of Health GenTAC program, which includes the Perelman School of Medicine at the University of Pennsylvania, Johns Hopkins University School of Medicine, Weill Cornell Medical College of Cornell University and Oregon Health and Science University.

The discovery was made possible by a grant from the NIH that funded the Specialized Center for Clinically Oriented Research in Aortic Diseases, a multi-institutional collaboration in the Texas Medical Center. The title of the article is “Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1.”

Merry-Lynn N. McDonald, Ph.D., at BCM; and Dong-chuan Guo, Ph.D., assistant professor of internal medicine at UTHealth, contributed equally along with LeMaire as co-first authors on the article.

Other UTHealth co-authors include Charles C. Miller, III, Ph.D., professor of cardiothoracic and vascular surgery; Ralph J. Johnson, Ph.D., assistant professor of internal medicine; Hazim Safi, M.D., professor and chair of the Department of Cardiothoracic and Vascular Surgery; and Anthony L. Estrera, M.D., professor of cardiothoracic and vascular surgery.

BCM co-investigators include Suzanne M. Leal, Ph.D., professor of molecular and human genetics; John W. Belmont, M.D., Ph.D., professor of molecular and human genetics; Ludivine Russell, M.S., cardiothoracic surgery research coordinator; Mir Reza Bekheirnia, M.D., clinical fellow in the Department of Molecular and Human Genetics; Luis M. Franco, M.D., assistant professor of molecular and human genetics; Mary Nguyen, B.S., cardiothoracic surgery laboratory technician; Molly Bray, Ph.D., associate professor of pediatrics; and Joseph S. Coselli, M.D., professor and chief of the Division of Cardiothoracic Surgery. Harvard Medical School co-investigators are Simon C. Body, M.B., Ch.B., M.P.H., associate professor of anesthesia; Christine Seidman, M.D., professor of genetics and medicine; Jonathan G. Seidman, Ph.D., professor of genetics; and Eric M. Isselbacher, M.D., associate professor medicine.  

Other co-investigators are Reed E. Pyeritz, M.D., Ph.D., Perelman School of Medicine at the University of Pennsylvania; Joseph E. Bavaria, M.D., Perelman School of Medicine at the University of Pennsylvania; Richard Devereux, M.D., Weill Cornell Medical College; Cheryl Maslen, Ph.D., Oregon Health and Science University; Kathryn W. Holmes, Johns Hopkins University School of Medicine, M.D., M.P.H; and Kim Eagle, M.D., University of Michigan Medical School.


 

 


 

 

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