Genetics of Aortic Aneurysmal Disease


Aortic aneurysmal disease may affect the thoracic and abdominal segments, but the pathophysiology and genetic causal background differ significantly. Abdominal aortic aneurysms (AAAs) are multifactorial and polygenic, whereas thoracic aortic aneurysms and dissections (TAAD) are typically familial and/or associated with certain syndromes. Various genomic loci have been linked to both diseases. Syndromic and nonsyndromic TAADs are the result of large‐effect gene mutations in genes controlling extracellular matrix (ECM) structure, transforming growth factor‐beta signalling and vascular cell contraction. AAA predisposition is determined by many small‐effect genomic loci involved in inflammation, lipid metabolism, ECM remodelling and vascular cell apoptosis. Nongenetic risk factors are also very important in AAA pathophysiology. Surgical management/repair is currently the only available treatment to prevent aneurysmal rupture. Functional genetic and epigenetic studies may result in the successful management of patients at risk, or ideally a medical treatment to prevent or cure aneurysmal disease.

Key Concepts

  • Aortic aneurysmal disease represents a condition that develops at two main regions in the aorta: thoracic aortic aneurysm and abdominal aortic aneurysm (TAA and AAA).
  • TAA is a risk factor of, and often coexists with, thoracic aortic dissection, which is also a medical emergency and can result in death, usually referred to together as thoracic aortic aneurysm and dissection (TAAD).
  • There is currently no effective pharmacotherapeutic strategy for either disease, and the only treatment option available is surgical repair to prevent rupture. Emergency repair, once rupture has occurred, is associated with adverse outcomes compared to elective surgery.
  • The pathophysiology between AAA and TAAD is different due to differences in composition between the two aortic regions, which is reflected in different genetic causal backgrounds.
  • AAA is more common than TAAD and has a multifactorial and polygenic basis of disease, whereas familial and syndromic TAAD is predominantly genetic.
  • High‐profile genome‐wide association studies using large sample sizes have discovered several small‐effect genomic risk loci involved in AAA development.
  • Genetic studies of syndromic and nonsyndromic TAAD, usually in the form of family linkage studies with generally low sample numbers, have yielded several high‐effect gene mutations involved in disease development.
  • The ongoing study of the functional genetic and epigenetic basis of TAAD and AAA could potentially result in better identification, intervention and clinical outcomes for patients.

Keywords: abdominal aortic aneurysm; thoracic aortic aneurysm; genome‐wide association study; cardiovascular disease; inflammation; vascular smooth muscle cell; extracellular matrix; multifactorial; polygenic

Figure 1. (a) Labelled representation of abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm and dissection (TAAD) sites of development in relation to the whole aorta. TAAD can develop in the aortic root, ascending aorta or less frequently the arch and descending aorta. (b) Labelled cross section of the structure of the aorta. The epidemiology, risk factors and genetic basis of disease are different between AAA and TAAD mainly due to the change in composition of the aortic wall from thoracic to abdominal regions, with the thoracic having a larger concentration of elastin, enabling it to withstand the increased pulse pressure exerted against it and allowing conformational dilation during systole and contraction during diastole. The thoracic regions of the aorta are derived from the neural crest during development, whereas the abdominal aorta has a mesodermal origin. In addition, the physiological composition of collagen to elastin ratio decreases from the ascending aorta through the descending aorta, while the media becomes thinner.
Figure 2. Karyotype schema of abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm and dissection (TAAD) risk loci. All the genes highlighted in this article that are implicated in AAA or TAAD are listed in a colour‐coded karyotype‐like schema. AAA risk loci are illustrated in red, syndromic TAAD in blue and nonsyndromic TAAD in green.


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Further Reading

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Toghill, Bradley J, Saratzis, Athanasios, Liyanage, Lakmini S, Sidloff, David, and Bown, Matthew J(Nov 2016) Genetics of Aortic Aneurysmal Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026851]