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Gene mutations influence risk of thoracic aortic disease severity, according to UTHealth Houston research

Dianna Milewicz, MD, PhD
Dianna Milewicz, MD, PhD

By comparing the risk of the first aortic surgical or medical event for patients with the gene mutation they carry, researchers with UTHealth Houston were able to tell which of seven common genes associated with thoracic aortic disease were more likely to lead to earlier, aggressive disease and death.

The research was published in the Journal of the American College of Cardiology.

“By identifying genes that predispose people to early disease, which can start in childhood, we are able to manage to direct more aggressive management, like imaging, medications, and surgery,” said Dianna Milewicz, MD. PhD, senior author and professor and director of the Division of Medical Genetics at McGovern Medical School at UTHealth Houston. “In contrast, some genes lead to later onset aortic events, and we do not need to manage these patients aggressively when they are young. Importantly, we can prevent deaths associated with thoracic aortic aneurysms and dissections if the patient is managed correctly. This data allows us to be more precise in our management, but also more cost-effective.”

In thoracic aortic disease, the aorta – the main artery that carries blood out of the heart to the lungs – develops a weakening in the lining that can balloon into an aneurysm or develop a tear. If the aneurysm tears, it leads to a dissection and sudden death. The disease led to the death of beloved comedian John Ritter. Milewicz, whose team has now discovered 20 gene alternations linked to the disease, leads the John Ritter Research Program at UTHealth Houston.

Researchers used the international Montalcino Aortic Consortium data from 1,028 individuals in 376 families with 218 unique variants in seven genes related to heritable thoracic aortic disease. Heritable disease runs in families with offspring having a 50-50 chance of carrying the gene alternation that leads to disease.

Along with prescribing medications, physicians monitor the size of aortas among family members who carry the gene mutation and surgery is performed to repair the aorta before a dissection or rupture occurs, thus preventing the deaths associated with acute aortic dissections.

The genes in the study included ACTA2 variants (30% of patients), TGFBR2 (23%), SMAD3 (20%), TGFBR1 (14%), MYLK (5%), PRKG1 (4%), and TGFB2 (4%).

The first aortic event was defined as an elective aortic aneurysm surgery or any aortic dissection. The median age for a first event was 36 years of age.

Patients with the PRKG1 mutation were associated with the highest risk for any aortic dissection or aortic event. The ACTA2, MYLK, and PRKG1 variants had a higher risk of presenting with Type A dissections located in the arch of the aorta.

Mutations in TGFBR1 and TGFBR2 had the highest burden of childhood-onset aortic events and in the case of some variants, monitoring of the aorta should begin in the first decade of life, according to the researchers.

The PRKG1 variant was associated with dissections at significantly younger ages than aneurysm repair, as well as Type A dissections with little to no enlargement of the aorta, making repair more difficult to time.

This information can assist physicians in making clinical decisions about patients with thoracic aortic disease.

“This comparison allows us to monitor when the disease could first present in a patient, and how quickly it may progress,” said Milewicz, the President George Bush Chair in Cardiovascular Medicine, vice chair of the Department of Internal Medicine, and director of the John Ritter Research Program at UTHealth Houston. “We are able to put that data together and come up with treatment guidelines.”

The research was funded by the National Institutes of Health (R01HL109942 and K23HL127266), Genetic Aortic Disorders Association Canada, Temerty Family Foundation, and the John Ritter Foundation.

First author was for the paper, titled “Comparative Risks of Initial Aortic Events Associated with Genetic Thoracic Aortic Disease,” was Ellen Regalado, PhD, of McGovern Medical School, UTHealth Houston.

Milewicz is also a member of The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences.

Coauthors included Shaine A. Morris, MD, MPH, Baylor College of Medicine; Alan Braverman, MD, Washington University School of Medicine; Ellen M. Hostetler, BA, McGovern Medical School at UTHealth Houston; Julie De Backer, MD, PhD, Ghent University Hospital, Belgium; Ruosha Li, PhD, UTHealth Houston School of Public Health; Reed E. Pyeritz, MD, PhD, University of Pennsylvania; Anji T. Yetman, MD, University of Nebraska Medical Center; Elena Cervi, MD, Great Ormond Street Hospital for Children, London; Sherene Shalhub, MD, University of Washington; Richmond Jeremy, MB, BS, PhD, University of Sydney, Australia; Scott LeMaire, MD, Baylor College of Medicine; Maral Ouzounian, MD, PhD, University of Toronto, Canada; Arturo Evangelista, MD, Vall d’Hebron Research Institute, Spain; and Catherine Boileau, PhD, and Guillaume Jondeau, MD, PhD, Université de Paris, France.

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