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Genetic Risk Factors for Abdominal Aortic Aneurysms (AAA)
17
and 423 controls were genotyped for 12 polymorphisms in 10 genes. The investigators found
that the presence of three or more genetic risk conditions was a strong and independent
determinant of AAA disease (OR = 2.96; 95% CI: 1.67 - 5.24; p < .0001). Moreover, the
value of genetic risk factors will be exponentially greater when combined with epidemiologic
data. The additive value of genomic data when combined with clinical characteristics has
already begun to be explored in the study of intracranial aneurysms. In a GWAS of 406
intracranial aneurysm cases and 392 control subjects, Deka et al. [
128] found evidence of
association with intracranial aneurysms and the SNP rs10958409 (OR = 1.86; 95%CI: 1.40 -
2.47). Furthermore, there was a multiplicative relationship between the risk allele and
smoking with regard to the risk of intracranial aneurysms (risk allele + 20 year smoking
history: OR = 5.04; 95%CI; 3.50 - 7.61). Progressing further, in a similar manner to the
intracranial aneurysm literature [129], genomic studies of AAA will lead to characterization
of AAA vulnerability to rupture and may be used as an aid to predict adverse cardiovascular
events following elective aneurysm repair.
6.2. Functional Studies to Elucidate Biological Mechanisms
Most of the SNPs identified in genome-wide studies and associated with AAA are
located far from any known genes and extensive molecular biological studies are required to
elucidate their role in AAA pathogenesis. For example, the best candidate gene in the
chromosome 9 region associated with AAA, coronary artery disease and many other vascular
and non-vascular phenotypes is a non-coding RNA gene CDKN2BAS, also known as ANRIL.
In mice, a deletion of a 70 kbp region encompassing the associated SNP (rs10757278) and
portions of the CDKN2BAS gene, but not the two closest protein coding genes CDKN2A and
CDKN2B, reduces cardiac and vascular expression of CDKN2A and CDKN2B [130].
Cultured smooth muscle cells from the aortas of these mice proliferated about twice as fast as
those from controls of the same strain, and did not show signs of senescence [130].
In another study based on experiments carried out in cultured human umbilical vein
endothelial cells, the chromosome 9p21.3 locus was implicated in the transcriptional control
of responses to the pro-inflammatory cytokine interferon via binding of a transcription factor
STAT1 [131]. The most comprehensive study related to the role of 9p21 locus in aortic
aneurysms found that Cdkn2b knock-out mice develop larger aortic aneurysms than control
mice with functional Cdkn2b gene in the elastase infusion model of AAA [118]. These mice
also demonstrated increased cellular proliferation in response to vessel wall injury, but had
fewer smooth muscle cells and increased apoptosis in the aortic wall [118]. In a cell culture
model, knock-down of CDKN2B resulted in increased expression of p53 and p21, molecules
known to promote apoptosis. In a histological analysis of human aortic samples, the
CDKN2B expression was seen mostly in smooth muscle cells and was reduced in AAA
[118]. Another interesting finding was that CDKN2BAS is able to suppress CDKN2B
expression epigenetically [132].
Re-sequencing of the 9p21.3 region in approximately 300 individuals from the
Framingham study identified 1,363 biallelic and 55 complex variants, 72% of which were
novel and not present in dbSNP build 128 and very rare [133]. Also, none of the variants with
at least 0.75% frequency of the minor allele had any obvious effect on protein function or
RNA splicing. A subset of these variants were selected for follow-up studies which included
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Helena Kuivaniemi, Evan J. Ryer, H. Richard Yoon et al.
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testing their association with aortic diameter. The most significant association was found with
rs4977574.
In conclusion, the current working hypothesis is that individuals with the risk allele at the
9p21 locus have lower expression of CDKN2B which enhances p53-dependent apoptosis and
leads to thinning of the media layer of the aortic wall making it more susceptible for dilatation
[
118]. Details of the mechanism and how to interfere it pharmacologically will provide
exciting new translational research opportunities.
CONCLUSION
AAAs are often asymptomatic, and if untreated, grow and lead to a sudden death due to a
rupture [134]. They can be diagnosed effectively using a non-invasive method,
ultrasonography screening [135], but the problem is that many patients are not referred to
screening even though studies have shown that this screening is not only life-saving, but also
cost-effective [136]. Implementation of web-based clinical decision support systems for
primary care physicians has shown to improve referrals to screening [137]. Another
alternative is to train family physicians, especially in the rural areas, to perform
ultrasonography examination to find AAAs [138]. Risk stratification of patients to those most
benefitting from screening could also improve compliance [7]. In the future genomically-
enhanced risk scores identifying individuals at increased risk for developing AAAs could
motivate patients to undergo screening. Such risk scores could also help to identify
individuals whose AAAs are likely to grow fast and lead to a rupture, necessitating closer
follow-up. Finally, deciphering the genetic mechanisms of AAAs would also facilitate the
design of new pharmacological treatment options for AAA to slow down the growth and
prevent rupture.
ACKNOWLEDGEMENTS
The original work by the authors and their collaborators was funded in part by the
National Heart, Lung, and Blood Institute, NIH (HL045996 and HL06410), the Pennsylvania
Commonwealth Universal Research Enhancement program, the Geisinger Clinical Research
Fund, the American Heart Association, and the Ben Franklin Technology Development Fund
of Pennsylvania. We gratefully acknowledge the work of our co-workers and collaborators.
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