Log in to MyACC
Genetic Determinants of Thoracic Aortic Size
Quick Takes
- In a study using data from the UK biobank and deep learning-derived measurements of the LVOT and aorta, 79 genetic loci were identified with significant association with ≥1 of the 8 assessed diameters.
- A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction was most strongly associated with thoracic aortic aneurysm.
- A polygenic score predicting a smaller aortic root was predictive of aortic stenosis.
Study Questions:
What is the genetic basis for the diameter of the left ventricular outflow tract (LVOT), aortic root, and ascending aorta?
Methods:
The UK Biobank is a population-based cohort of 500,000 individuals aged 40–69 years. Using deep learning, 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants were analyzed. The diameters of the LVOT, the aortic root, and at six locations of the ascending aorta relative to participant height were computed. For each diameter, a genome-wide association study was conducted, and a polygenic score was generated. Associations between these scores and disease incidence were investigated.
Results:
A total of 79 loci were significantly associated with ≥1 of the 8 assessed diameters, of which 35 were novel; 41 loci were significantly associated with 1 or 2 diameters, and 26 were associated with ≥4 diameters. A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm (n = 427,016; mean hazard ratio [HR], 1.42 per standard deviation [SD]; 95% confidence interval [CI], 1.34-1.50; p = 6.67 x 10–21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n = 426,502; mean HR, 1.08 per SD; 95% CI, 1.03-1.12; p = 5 x 10–6).
Conclusions:
Distinct genetic loci underpinning the diameters of the LVOT, aortic root, and at several segments of ascending aorta were detected; a region of the aorta with genetics potentially most relevant to predicting thoracic aortic aneurysm was spatially defined; and a genetic signature that may predispose to aortic stenosis was described. The authors concluded that understanding genetic contributions to proximal aortic diameter may enable identification of individuals at risk for aortic disease and facilitate prioritization of therapeutic targets.
Perspective:
The ascending aorta is developmentally complex, arising from two separate germ layers. In addition, abnormalities of the aortic valve and the ascending aorta are influenced by acquired comorbidities including hypertension and atherosclerosis. This study, based on a large biometric database that contains genetic and health information from 500,000 UK participants, found 79 genetic loci associated with ≥1 diameter in the LVOT, aortic root, and ascending aorta; a polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predictive of thoracic aortic aneurysm; and a polygenic score predicting a smaller aortic root associated with aortic stenosis.
The study is limited by a potentially nonrepresentative population (of predominantly European ancestry and healthier than the general population), the use of machine learning to obtain LVOT and aortic measurements, and the use of hospital-based diagnostic and procedural codes to identify disease. It is not clear from the manuscript how comorbidities such as hypertension and atherosclerotic disease were investigated as contributing factors for the acquired diseases of aortic aneurysm and aortic stenosis, or whether a small LVOT measurement might have been responsible for a diagnosis of aortic stenosis owing to its use in the continuity equation for aortic valve area. Although interesting, the study leaves open questions about the interactions between genetics and acquired comorbidities in the expression of diseases of the thoracic aorta and the aortic valve.
Clinical Topics: Cardiac Surgery, Noninvasive Imaging, Prevention, Valvular Heart Disease, Vascular Medicine, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and VHD, Magnetic Resonance Imaging, Hypertension
Keywords: Aortic Aneurysm, Aortic Aneurysm, Thoracic, Aortic Valve Stenosis, Atherosclerosis, Constriction, Pathologic, Deep Learning, Diagnostic Imaging, Genetic Loci, Genome-Wide Association Study, Heart Valve Diseases, Hypertension, Magnetic Resonance Imaging, Cine, Multifactorial Inheritance, Risk, Secondary Prevention, Vascular Diseases
< Back to Listings
