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Diagnoses of bicuspid aortic valve (BAV), thoracic aortic aneurysm, and thoracic aortic dissection appeared to run in families extending beyond first-degree relatives, according to the largest pedigree-based study on the subject to date.

Among probands with BAV and aortopathy in the Utah Population Database, first-degree relatives were several times more likely to share a concordant diagnosis compared with peers lacking family members with these conditions:

• First-degree relatives of patients with BAV: HR 6.88, 95% CI 5.62-8.43
• First-degree relatives of patients with thoracic aortic aneurysm: HR 5.09, 95% CI 3.80-6.82
• First-degree relatives of patients with thoracic aortic dissection: HR 4.15, 95% CI 3.25-5.31

"To successfully understand the complex pathogenetics of thoracic aortic disease and BAV, large-population and pedigree-based data sets need to be developed and linked to large-scale genomic studies in susceptible patients. The present study represents an initial step in this larger effort," wrote investigators led by Jason Glotzbach, MD, a cardiac surgeon at the University of Utah Health in Salt Lake City, in .

As individuals were further away from the proband on the family tree, they were less likely to have the same diagnosis, they noted. "In general, heritability of a given phenotype increases when the dose-response nature of the observed effect demonstrates increasing risk with increasing degrees of relatedness."

"Based on the results of this study, there are likely many asymptomatic individuals for whom a diagnosis of thoracic aortic disease has not been established but who are at increased risk for aortic complications and mortality," Glotzbach and team wrote. "The observed familial relative risk in this study across a large population provides evidence in support of routine screening evaluations of the family members of affected individuals."

U.S. guidelines currently recommend screening of first-degree relatives of people with BAV or thoracic aortic disease.

Based on the present study, "it would be prudent to consider the expansion of screening regimens to include more distant relatives of patients with BAV, thoracic aortic aneurysms, and thoracic aortic dissection, especially in families with >1 member affected," the authors noted.

Their observational case-control study relied on the Utah Population Database, which covers most people who have ever lived in Utah and contains genealogy, residential history, and medical and administrative data.

The study included 14,731 probands with aortic conditions (median birth year 1939; 54% men) who were pooled 1:10 with age- and sex-matched controls. First-degree relatives, second-degree relatives, and first cousins of probands and controls were also identified, yielding over 3.6 million unique relatives for analysis.

Glotzbach and colleagues reported that the familial risk of aortic diagnoses in the Utah cohort extends to excess mortality risk, as first-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality compared with controls (HR 2.83, 95% CI 2.44-3.29). A smaller effect was seen in second-degree relatives and first cousins.

In addition, compared with controls, the risk of aortic dissection was higher in:

• First-degree relatives of patients with BAV: HR 3.63, 95% CI 2.68-4.91
• First-degree relatives of patients with thoracic aneurysm: HR 3.89, 95% CI 2.93-5.18
• First-degree relatives of patients with a diagnosis of both BAV and aneurysm: HR 6.13, 95% CI 2.82-13.33

Glotzbach and colleagues acknowledged that their observational analysis may be subject to unrecognized or uncontrolled biases. "We cannot determine causation from these results, and further investigative work will be necessary by our group and others to further elucidate the potential causal relationship between familiality and genetics to the development and progression of BAV and aortic disease," they wrote.

Additionally, the results relied on aortic diagnosis records being comprehensive and accurate. What's more, their generalizability to other populations is unknown, they said.

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