Genetics of Thoracic and Abdominal Aortic Diseases

Abstract

Dissections or ruptures of aortic aneurysms remain a leading cause of death in the developed world, with the majority of deaths being preventable if individuals at risk are identified and properly managed. Genetic variants predispose individuals to these aortic diseases. In the case of thoracic aortic aneurysm and dissections (thoracic aortic disease), genetic data can be used to identify some at-risk individuals and dictate management of the associated vascular disease. For abdominal aortic aneurysms, genetic associations have been identified, which provide insight on the molecular pathogenesis but cannot be used clinically yet to identify individuals at risk for abdominal aortic aneurysms. This compendium will discuss our current understanding of the genetic basis of thoracic aortic disease and abdominal aortic aneurysm disease. Although both diseases share several pathogenic similarities, including proteolytic elastic tissue degeneration and smooth muscle dysfunction, they also have several distinct differences, including population prevalence and modes of inheritance.

Keywords: aorta; aortic aneurysm; genes; genetic association studies; mutation; prevalence; rupture.

Figure 1:

Thoracic aortic disease risk associated to variant frequencies (adapted from Manolio et al 2009).

Figure 2:

Schematic representation of thoracic aortic aneurysms and aortic dissections.

Figure 3:

Schematic representation elastin lamellae and SMCs highlighting the proteins that are disrupted by mutations in genes, leading to heritable thoracic aortic disease. Extensions from the elastin lamellae with fibrillin-1-containing microfibrils at the end link to integrin receptors on the cell surface of SMCs. The integrin receptors then link to the contractile filaments inside the cells, thus forming the elastin-contractile unit. Also illustrated is the proteins involved in canonical TGF-β signaling that are disrupted by mutations in the corresponding genes to also lead to heritable thoracic aortic disease. The validated genes predisposing to thoracic aortic disease are shown in red and are adjacent to their corresponding protein. MLCK; myosin light chain kinase; PKG-1, type I cGMP-dependent protein kinase. (Illustration Credit: Ben Smith).

Figure 4:. A proposed mechanism by which mechanotransduction or mechanosensing across the elastin-contractile units predispose to thoracic aortic disease.

Thoracic aortic aneurysms and dissections are driven by environmental factors, such as hypertension (HTN), or mutations that disrupt proteins that are components of elastin-contractile units. In the case of gene mutations, the elastin-contractile unit is predicted or has been shown to be disrupted,^, and thus may upregulate cellular pathways in SMCs that lead to disease. In terms of hypertension triggering thoracic aortic disease, the elastin-contractile unit may not be disrupted, or may be only altered in a minor way, but the hypertension increases the forces across the elastin-contractile unit, potentially activating the same downstream pathways leading to thoracic aortic aneurysms and dissections.