Disease summary:

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  Abdominal aortic aneurysms (AAAs), defined as dilatations of the aorta, are a complex disease with both genetic and environmental risk factors.

  
  
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  Prevalence: 1% to 2% of Caucasian populations harbor AAAs in industrialized countries. Prevalence increases with age to about 10% among men over 65 years of age.

  
  
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  AAA is the 17th leading cause of death in the United States, with approximately 15,000 deaths per year.

  
  
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  Risk factors: The most important known risk factors are smoking, positive family history, advanced age, and male sex. Elevated cholesterol levels and hypertension are mild risk factors. Diabetes, African-American ethnicity, and female sex are protective factors.

  
  
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  AAAs have a complex, poorly understood pathophysiology, in which inflammation, smooth muscle cell apoptosis, reactive oxygen species, extracellular matrix degradation, and activation of matrix metalloproteinases play a role.

Differential diagnosis:

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  Diverticulitis, renal colic, and gastrointestinal hemorrhage belong to the differential diagnosis of ruptured AAA.

Monogenic forms:

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  Aortic aneurysms can be found in patients with the Ehlers-Danlos syndrome type IV, the Marfan syndrome, and fibromuscular dysplasia. These Mendelian diseases are far less common than AAA and patients with these diseases constitute only a very small fraction of AAA patients, representing a rare form of AAA.

Family history:

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  Family history of AAA is an important risk factor for AAA with an odds ratio (OR) = 1.96 (95% CI: 1.68-2.28) determined in population-based screening studies. Two formal segregation analyses have been published for AAA. Both studies demonstrated statistically significant evidence for a genetic model. In one study an autosomal recessive model for a major gene had the best fit, whereas in the other study an autosomal dominant model for a major gene was the best fit for the familial aggregation of AAA in their sample. A third report, in which a large collection of AAA families with 233 multiplex families was described, found that 72% of the AAA families were consistent with an autosomal recessive pattern, while 25% showed an autosomal dominant pattern of inheritance. Not finding a single mode of inheritance is consistent with AAA being a multifactorial disease where different loci can have distinct modes of inheritance.

Twin studies:

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  Only four case reports on twins with AAA have been published.

Environmental factors:

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  Smoking is the most important identified risk factor with an OR = 3.34 (95% CI: 3.04-3.67) for men and 3.80 (95% CI: 1.57-9.20) for women with a history of smoking.

DNA linkage studies:

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  Shibamura and colleagues studied 119 AAA families using an affected relative pair (ARP) approach with sex and number of affected relatives, and their interactions as covariates, allowing for genetic heterogeneity. Using a two-phase, two-stage study design, a whole genome scan was completed using approximately 400 microsatellite markers. The first phase analyzed 36 multiplex families with 78 ARPs using sex and the number of first-degree relatives as covariates. Twelve regions on eight chromosomes (3, 4, 5, 6, 9, 14, 19, 21) were identified as being worthy of follow-up with p less than 0.05. The second stage of phase 1 was to genotype additional markers in regions giving positive results. Phase 2 included testing of positive markers in 83 new multiplex families, which included 157 ARPs. After detailed follow-up analysis with a combined set of 235 ARPs, significant linkage was found on chromosomes 4q31 (LOD score = 3.73, p = .0012) and 19q13 (LOD score = 4.75, p = .00014). These genomic regions have been designated as AAA2 and AAA1 susceptibility loci, respectively, in Online Mendelian Inheritance in Man (OMIM). In addition, a second locus on chromosome 4, at 4q12, had a LOD of 3.13 (p = .0042).

Genome-wide associations:

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  Elmore and colleagues carried out a genome-wide genetic association study (GWAS) for AAAs using pooled DNA samples and a case-control design. They found a haplotype on chromosome 3p12.3 associated with AAA. One single-nucleotide polymorphism (SNP) in this region (rs7635818) was genotyped in a total of 502 cases and 736 controls from the original study population (p = .017) and 448 cases and 410 controls from an independent replication sample (p = .013; combined p = .0028; combined OR = 1.33). An even stronger association with AAA was observed in a subset of smokers (391 cases, 241 controls, p = .00041, OR = 1.80), which represent the highest-risk group for AAA. The AAA-associated haplotype is located 200 kbp upstream of the CNTN3 gene transcription start site.

Other significant genetic studies:

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  Using 2836 AAA cases and 16,732 controls, a large consortium tested a variant, rs10757278, discovered from another GWAS on coronary artery disease, in five different vascular phenotypes: coronary artery disease, peripheral arterial disease, atherosclerotic stroke, intracranial aneurysms, and AAA. The SNP rs10757278 was associated with AAA (p = 1.2 × 10⁻¹²; OR = 1.31, 95% CI: 1.22-1.42). This is the first genetic variant associated with AAA, intracranial aneurysms and other cardiovascular diseases and it suggests a common pathway in vascular disease etiology. The SNP rs10757278 is located on chromosome 9p21 in a gene called ANRIL, a noncoding RNA. It is of interest that another SNP, rs10811661, known to be associated with type 2 diabetes and located 10 kb away from rs10757278, was not associated with AAA. This finding is in agreement with epidemiologic data demonstrating that diabetes is not a risk factor for AAA.