https://orcid.org/0000-0001-6088-4037
Abstract
This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone.
Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants.
AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%–41.8%) vs. 29.3% (27.0%–31.5%) in UK Biobank, 36.5% (34.4%–38.5%) vs. 32.5% (30.4%–34.5%) in MGB, 41.8% (37.7%–45.9%) vs. 33.0% (28.9%–37.2%) in FHS, and 34.9% (28.8%–41.0%) vs. 28.9% (22.9%–35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P < .0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P < .0001), 0.856 vs. 0.818 in FHS (P < .0001), and 0.827 vs. 0.791 (P = .0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P = .0042) and All of Us (P = .049).
A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%–41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors.
A clinical model to estimate ascending aortic diameter was developed in 44 420 UK Biobank participants with cardiovascular magnetic resonance imaging, with the arrows depicting interaction terms between the clinical risk factors. A polygenic score derived from a genome-wide association study of 39 524 participants was incorporated based on data from 4896 participants to produce the AORTA Gene model. The AORTA Gene model was used to estimate ascending aortic diameter in UK Biobank, All of Us, Framingham Heart Study, and Mass General Brigham and to predict adverse thoracic aortic outcomes, including thoracic aortic dissection, in UK Biobank and All of Us. The aortic drawings are derived from Servier Medical Art, CC BY 4.0. Height image by Fengquan Li, aging image by Adrien Coquet, blood pressure cuff image by Luis Prado, scale image by Gacem Tachfin, and DNA image by TkBt, from thenounproject.com, CC BY 3.0. FHS, Framingham Heart Study; GWAS, genome-wide association study; MGB, Mass General Brigham.
