Genes and abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since the first candidate gene studies were published 20 years ago, approximately 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. These 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, only when 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 contactin-3, which is located on chromosome 3p12.3. However, two follow-up studies could not replicate this 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 ribonucleic acid that regulates expression of the cyclin-dependent 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 toward AAA pathogenesis.

Fig. 1

Summary on the biological pathways thought to be involved in AAA pathogenesis. The genes investigated for conferring genetic risk for AAA can be divided into five different functional groups. Genes with best evidence for contributing to AAA pathogenesis are shown in green. Studies on these genes had sufficient numbers of cases and controls making it likely that the results are not false positive associations. Details on the results of each gene are provided in Tables II through VI. To make it easier to find the genes in each functional group we have alphabetized the gene symbols, which are available from the National Center for Biotechnology Information (NCBI; http://www.ncbi.nlm.nih.gov/).