The genetic basis for aortic aneurysmal disease

Abstract

Aortic aneurysms are an important cause of cardiovascular death in elderly patients. At present, little is known of the pathobiology of aneurysmal disease and this limits the ability to develop non-surgical treatments to stabilise aneurysms. Both thoracic and abdominal aortic aneurysms (AAA) demonstrate a strong genetic component in their aetiology. Determination of the genetic variants associated with aneurysmal disease is one approach to increasing the understanding the pathways leading to aneurysmal degeneration of the aorta. In this review, we aim to summarise the current knowledge of the genetics underlying the two most common disease phenotypes, thoracic aortic aneurysm (TAA) and AAA. Genetically, AAA represent a multifactorial disease, with the likelihood that there are multiple variants of very low effect sizes contributing to the overall genetic disease risk. Non-syndromic TAA appears to be associated with a smaller number of risk loci with higher individual effect sizes at these loci. Candidate gene and genome-wide approaches have identified robust associations between AAA and variants in/nearby the SORT1, low-density lipoprotein receptor, DAB2IP, LRP1, ELN, CRP, TGFB and various matrix metallo-proteinase genes suggesting that aberrations of lipid metabolism and proteolytic pathways are the key contributors to disease. Some of these associations (eg, LRP1) are not associated with atherosclerosis, suggesting pathways unique to AAA. Genetic variants associated with non-syndromic TAA (ACTA2 and MYH11) are related to the TGFβ pathway, strongly implicated in syndromic TAA, thus suggesting a common pathway between syndromic and non-syndromic TAA.

Patients with Small Abdominal Aortic Aneurysm are at Significant Risk of Cardiovascular Events and this Risk is not Addressed Sufficiently

“…Aneurysmal and CV disease share common risk factors (16,17). It is therefore rational to suggest that patients with AAA will be at increased risk of CV events, even before the AAA merits surgical-intervention.…”

Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants

“…Underlying genetic factors contributing to two diseases also differ based on the site of the clinical manifestation, as well as their weight (see Fig. 1) [1,[5][6][7]. Accordingly, it has been evidenced that genetic determinants may influence AAA development.…”

Prevalence of abdominal aortic aneurysms and its relation with cardiovascular risk stratification: protocol of the Risk of Cardiovascular diseases and abdominal aortic Aneurysm in Varese (RoCAV) population based study

“…The large set of data collected in the RoCAV study, their novelty (PWV, ABI, diet scores), the validated tools used, the possibility to measure new biomarkers in samples stored in biobank (metabolomics and proteomics) will address this question. Furthermore, it is expected than a large impact would have epigenetic and genetic mechanisms [17, 18], alone or in interaction with environmental variables, both measurable in biobank samples. Therefore, the availability of this large set of data will allow to model an AAA risk score algorithm for risk assessment, potentially useful to select subgroups of patients at higher risk to be included in a screening program, as for risk stratification of major CVD.…”

“…For this reason, the use of standard CVD risk score as well as the presence of a previous CVD could be useful to select subgroups at higher risk to screen for AAA. However, part of the phenotypic variability in the population remains unexplained, probably due to other risk factors or to interactions with the genetic and epigenetic background [17, 18]. Population based studies with the availability of biobank samples could be useful to enlarge the focus on further biomarkers.…”