Genetic Risk Factors for Abdominal Aortic Aneurysms (AAA)
Document Type
Book Contribution
Publication Date
1-1-2015
Description
Abdominal aortic aneurysm (AAA) is a complex, multifactorial disease with a strong genetic component. About 20% of AAA patients have at least one relative with this condition. Since the 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 most significant results from candidate gene studies are for sortilin-1 (SORT1), interleukin 6 receptor (IL6R), and apolipoprotein(a) (LPA). Unbiased genome-wide approaches such as family-based DNA linkage studies and genome-wide association studies have been carried out by international consortia to identify susceptibility loci for AAA. The chromosomal regions in the human genome with the strongest supporting evidence of contribution to the genetic risk for AAA are: 1) CDKN2BAS gene (located on chromosome 9p21), also known as ANRIL, which encodes an antisense RNA that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B; 2) DAB2 interacting protein (DAB2IP; located on chromosome 9q33), which encodes an inhibitor of cell growth and survival; 3) low density lipoprotein receptor-related protein 1 (LRP1; located on chromosome 12q13.3), a plasma membrane receptor involved in vascular smooth muscle and macrophage endocytosis, 4) low density lipoprotein receptor (LDLR; located on chromosome 19p13.2), and 5) contactin-3 (CNTN3; located on chromosome 3p12.3), which demonstrated the strongest association in smokers and yet its function remains unclear. These five loci were identified in genome-wide association studies. Using a different approach, DNA linkage analysis with affected relative-pairs, two additional loci containing several plausible candidate genes, located on chromosomes 4q31 and 19q13, were discovered. On-going and future studies to find additional risk loci include large meta-analyses and whole genome sequencing. Furthermore, functional studies are needed to establish the mechanisms by which these genes contribute to AAA pathogenesis. In the long-term, these discoveries will result in important translational applications to the prevention, diagnosis and management of AAAs.
Citation Information
Kuivaniemi, Helena; Ryer, Evan J.; Yoon, H. Richard; Elmore, James R.; and Tromp, Gerard. 2015. Genetic Risk Factors for Abdominal Aortic Aneurysms (AAA). Horizons in World Cardiovascular Research. Vol.7 1-31. ISBN: 9781634638760,9781634638616