Abstract
BACKGROUND: Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. METHODS: In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. RESULTS: The study population included 3 812 588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [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]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25-5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68-4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93-5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82-13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44-3.29]) compared with controls. CONCLUSIONS: Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. This study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.
| Original language | English |
|---|---|
| Pages (from-to) | 637-647 |
| Number of pages | 11 |
| Journal | Circulation |
| Volume | 148 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 22 2023 |
Funding
The authors thank the University of Utah Surgical Population Analysis Research Core for its role in facilitating data collection, database management, and analysis. They also thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance, and support of the UPDB. They also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah, and from the University of Utah Personalized Health and Center for Clinical and Translational Science. J.P.G. takes full responsibility for all aspects of this study, including study design, data collection and integrity, and analysis, manuscript preparation, and revision. J.P.G., H.A.H., J.E.T., M.T.-F., and C.H.S. conceived study design. J.P.G., H.A.H., J.E.T., J.J.H., C.M.A., and A.P.P. performed data analysis. J.P.G., H.A.H., J.E.T., C.L.G., V.S., M.Z., M.T.-F., and C.H.S. drafted and edited the manuscript. All authors had final approval of the manuscript and are accountable for the work. Dr Glotzbach was supported by a surgical investigator grant from the American Association for Thoracic Surgery, by the National Institutes of Health loan repayment program, and by a National Institutes of Health National Heart, Lung, and Blood Institute award (K08HL165084). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Partial support for all data sets within the UPDB was provided by the University of Utah Huntsman Cancer Institute and a Huntsman Cancer Institute Cancer Center Support grant (P30 CA2014) from the National Cancer Institute. This article was written by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the US Department of Energy (DOE). The publisher, by accepting the article for publication, acknowledges that the US government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this article, or allow others to do so, for US government purposes. The US DOE will provide public access to these results of federally sponsored research in accordance with the US DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ).
Keywords
- aortic aneurysm
- aortic dissection
- bicuspid aortic valve disease
- risk assessment
- thoracic