The AORTA Gene score for detection and risk stratification of ascending aortic dilation

Abstract Background and Aims 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. Methods 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. Results 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). Conclusions 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.