Genes and Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since first candidate gene studies were published 20 years ago, nearly 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. The studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, if appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called CNTN3 which is located on chromosome 3p12.3. Two follow-up studies, however, could not replicate the association. Two other SNPs, which are located on chromosome 9p21 and 9q33 were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense RNA that regulates expression of the cyclindependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute to AAA pathogenesis.

Understanding the pathogenesis of abdominal aortic aneurysms

“…About 10–20% of AAA patients have at least one relative with this condition and formal segregation analyses have favored genetic models in explaining this familial aggregation [21,38,39,83]. The Swedish Twin registry, which contains data on all 172,890 twins born in Sweden since 1886, has 265 twins with an AAA [80].…”

“…Since the first candidate gene studies were published more than 20 years ago, over 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA [83]. More recently, unbiased genome-wide approaches such as family-based DNA linkage studies and genome-wide association studies (GWAS) have been carried out to identify susceptibility loci for AAA.…”

The genetic basis for aortic aneurysmal disease

“…Overall, only a small minority of the candidate gene-association studies (more than 100 studies analysing several functional and non-functional SNPs) published to date were sufficiently powered to draw firm conclusions and very few results could be replicated in different sample sets. Hinterseher et al32 provide an exhaustive review of all data available until recently (2011) regarding associations between specific SNPs and AAA presence in various populations. They have identified various associations of some significance, but the vast majority of the studies included have analysed populations of less than 150 individuals.…”

The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis

“…Three genome-wide association studies have individually identified three novel single nucleotide polymorphisms (SNPs) associated with AAA 5. These SNPs, however, account for only a small proportion of AAA heritability 6. Improved knowledge of the genetically determined susceptibility to AAA may provide insight into novel pharmacological targets for this condition and assist targeted population-based screening programmes.…”