REVIEW
URRENT
C
OPINION
Genetics of abdominal aortic aneurysm
Jonathan Golledge a and Helena Kuivaniemi b
Purpose of review
Family history is a risk factor for abdominal aortic aneurysm (AAA), suggesting that genetic factors play an
important role in AAA development, growth and rupture. Identification of these factors could improve
understanding of the AAA pathogenesis and be useful to identify at risk individuals.
Recent findings
Many approaches are used to examine genetic determinants of AAA, including genome-wide
association studies (GWAS) and DNA linkage studies. Two recent GWAS have identified genetic
markers associated with an increased risk of AAA located within the genes for DAB2 interacting protein
(DAB2IP) and low density lipoprotein receptor-related protein 1 (LRP1). In addition, a marker on 9p21
associated with other vascular diseases is also strongly associated with AAA. The exact means by which
these genes currently control AAA risk is not clear; however, in support of these findings, mice with
vascular smooth muscle cell deficiency of Lrp1 are prone to aneurysm development. Further current work is
concentrated on other molecular mechanisms relevant in AAA pathogenesis, including noncoding RNAs
such as microRNAs.
Summary
Current studies assessing genetic mechanisms for AAA have significant potential to identify novel
mechanisms involved in AAA pathogenesis of high relevance to better clinical management of the
disease.
Keywords
abdominal aortic aneurysm, genetic association studies, genetic susceptibility, microRNA, twin studies
INTRODUCTION
there is no medication which has been convincingly
shown to slow AAA progression [12 ]. There is, thus,
considerable interest in the mechanisms responsible
for AAA progression that could be targeted by drug
therapies to limit requirement for surgical intervention [1–3,12 ]. The goal of this review article is to
summarize the current knowledge on the contribution of genetic factors to AAA. We do not discuss
the genetics of thoracic aneurysms where a range of
monogenetic diseases have been implicated, such as
those involving mutations in fibrillin-1 and transforming growth factor b receptors.
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Abdominal aortic aneurysm (AAA) is a degenerative
condition associated with a risk of aortic rupture at
advanced stages [1–3]. AAA is defined as an abdominal aortic diameter of at least 30 mm, although the
risk of AAA rupture only becomes significant at
larger diameters, estimated as approximately 10
and 30%/year for AAAs measuring 55–69 and at
least 70 mm, respectively [4]. The most important
risk factors for AAA are smoking, family history of
AAA, older age, male sex, and coronary artery disease [1–3,5,6]. Population-based studies indicate
these factors individually increase risk of developing
an AAA by two-fold to five-fold [1,3]. Dyslipidemia
and hypertension are weaker positive risk factors
and diabetes a negative risk factor for AAA
[1–3,7 ]. Population screening has been introduced
in a number of countries to identify AAAs at an early
stage; however, endovascular or open surgical AAA
repair has not been shown to reduce mortality for
patients with small (diameter <55 mm) AAAs, which
are the main type of aneurysm identified by screening
[8–11]. Up to 70% of small AAAs progress to a size
where surgical treatment is needed and currently
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a
The Vascular Biology Unit, Queensland Research Centre for Peripheral
Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Australia and bSigfried and Janet Weis Center for
Research, Geisinger Clinic, Danville, Pennsylvania, USA
Correspondence to Jonathan Golledge, MChir, Professor of Vascular
Surgery, School of Medicine and Dentistry, James Cook University,
Townsville 4811, Australia. Tel: +61 7 4796 1417; fax: +61 7 4796
1401; e-mail: [email protected]
Curr Opin Cardiol 2013, 28:290–296
DOI:10.1097/HCO.0b013e32835f0d55
Volume 28 Number 3 May 2013
Genetics of abdominal aortic aneurysm Golledge and Kuivaniemi
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KEY POINTS
Genetic factors play an important role in AAA. On the
basis of a recent twin study the heritability of AAA is
estimated to be as high as 70%.
Recent GWAS have identified genetic loci associated
with AAA.
Advances in genomic technologies will enable the
identification of important new mechanisms in AAA
pathogenesis with potential for guiding development of
new treatments.
included formal segregation analyses [3,13 ], support genetic factors being important in AAA development.
GENES IMPLICATED IN THE INHERITED
RISK OF ABDOMINAL AORTIC ANEURYSM
Three approaches have been used in an attempt to
identify genetic variations responsible for an
increased risk of developing an AAA, and these
include candidate gene studies; genome-wide
DNA linkage studies; and genome-wide association
studies (GWAS) [3,13 ,14,18,19].
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ABDOMINAL AORTIC ANEURYSM AS A
GENETIC DISEASE
Genetic loci associated with familial
abdominal aortic aneurysm
In genetic epidemiology a stepwise approach is used
to examine the role of genetic factors in a disease.
First, evidence is sought to support that there is a
likely genetic component involved in the development of the disorder. Second, the relative size of the
genetic effect is estimated. Finally, studies are
designed to identify genes responsible for the inherited risk. There is an increasing body of strong
evidence demonstrating that genetic factors are
important in the development of AAA even when
they are not associated with rare, syndromic forms
of aneurysms. One of the challenges in defining the
genetic factors is the heterogeneous nature of the
patient population. AAAs are a complex disease, as
they develop as a composite of environmental risk
factors and genetic predisposition and present at an
older age [2,3,13 ,14].
Family history of AAA doubles a person’s risk
for AAA [1–3,13 ,15]. It is likely that genetic
factors also contribute to the various risk factors
for AAA such as atherosclerosis, hypertension,
dyslipidemia and smoking [1–3,13 ,14,16]. In a
recent study performed in Sweden using registry
data the requirement for in-patient treatment of
AAA in 265 twins was examined [17]. The estimated
odds ratio (95% confidence interval) of having
an AAA in monozygotic and dizygotic twins was
71 (27–183) and 8 (3–19), respectively. On the basis
of these data the investigators estimated a surprisingly high heritability (i.e. the proportion of the
variance attributable to genetic effects) of 70% for
AAA. Approximately 16% of the twins presented at
an age less than 55 years, suggesting some of these
cases may have included syndromic forms of aneurysmal diseases such as Marfan syndrome; however,
if these cases were excluded the odds ratios for
AAAs in monozygotic and dizygotic twins were
still very disparate at 36 and 5, respectively. Overall
these findings, together with previous studies that
Tracing family histories of patients who have AAAs is
not straightforward for a number of reasons, including the late age-at-onset of the disease, the low rate of
postmortems in most countries and the allocation of
most sudden deaths to cardiac causes. One way
around these problems is to study affected siblings
of AAA patients, who are usually of similar age. A
number of studies have highlighted the relatively
high incidence of AAA in siblings of AAA patients,
reporting rates of 9–29 and 0–11% in brothers and
sisters, respectively [3,13 ]. The most recent of these
studies was carried out in Sweden [20 ].
Genome-wide DNA linkage analyses using DNA
from families in which two or more members had an
AAA identified two genomic regions on chromosome 4q31 and 19q13 linked to AAA [21,22].
Whether such genetic loci include genetic risk
alleles for AAAs that developed in individuals with
no family history remains unknown. The genomic
region identified on chromosome 19q13 contains a
large number of known genes, one of which encodes
kallikrein 1 (KLK1), a serine protease that converts
low molecular weight kininogen to Lys-bradykinin,
a peptide that has a range of biological actions
relevant to AAA such as promotion of inflammation. Kinins act through binding to B1 and B2
receptors. Deficiency of the B1 receptor has been
reported to lead to an increased risk of AAA development in a mouse model [23]. In a recent study
involving 1629 patients the single nucleotide polymorphism (SNP) rs5516 in KLK1 was examined in
two independent groups of cases and controls that
had been imaged for AAA [24 ]. The G allele of
rs5516 was associated with large (50 mm) but
not small AAA in both populations although under
different modes of inheritance. This SNP is known to
control the expression of splicing variants of KLK1,
and indeed the expression of the short splice variant
of KLK1 was upregulated in tissue samples taken
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from large AAAs [24 ]. As the study included only
79 patients with large AAAs, replication of these
findings is needed. Another recent study examined
41 SNPs in nine other plausible candidate genes
within the chromosome 19q13 locus in 394 cases
and 419 controls [25]. Associations between SNPs in
genes encoding enhancer binding protein (CEBPG),
peptidase D (PEPD) and CD22 with AAA were found.
Larger studies examining the chromosome 4q31 and
19q13 loci are needed to confirm the findings and
identify more precisely the genetic loci involved.
Genetic loci associated with sporadic
abdominal aortic aneurysm
Most patients who develop AAA are not aware of
any family history of the condition. Most studies
examining genetic risk alleles for AAA have investigated SNPs in candidate genes within groups of
cases and controls without family history of AAA
[13 ]. These studies have reported an enormous
number of genetic variations associated with AAA;
however, in many cases these findings have not
been replicated in different studies and populations
[13 ]. Meta-analyses of these studies have suggested
that polymorphisms in the genes encoding angiotensin converting enzyme (ACE), 5,10-methyltetrahydrofolate reductase (MTHFR), angiotensin II
type 1 receptor (AGTR1), interleukin-10 (IL10),
matrix metallopeptidase-3 (MMP3) and transforming growth factor, b receptor II (TGFBR2) are associated with AAA [26,27 ]. A recent large multicenter
study found a highly significant association
between SNPs in the apolipoprotein(a) (LPA) gene
and AAA, although this association was lost after
exclusion of patients with coronary heart disease
[28 ]. It appears likely that the genetic predisposition for AAA is made up of small contributions from
a large number of risk alleles (many still unknown)
for which the effect size varies depending on the
population examined and the additional environmental risk factors incorporated in the models (see
recent reviews for further details [3,13 ,14,29,30]).
GWAS has been suggested as the most efficient
method to identify reproducible risk alleles predisposing to common complex diseases [31]. Typically,
more than 500 000 common SNPs are examined in
cases and controls to assess the association with the
disease under study [3,13 ,14,29–31]. These studies
need very large numbers of cases and controls to be
adequately powered to identify risk alleles with odds
ratios of approximately 1.2 and to enable adjustment for multiple testing. These studies, therefore,
usually require collaborations between multiple
groups, which introduces a number of complexities
and challenges. One of these challenges is the
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variation in phenotyping methods and techniques
used to define risk factors inevitably employed by
different investigators. Thus, for example, in some
groups imaging may have been used to differentiate
between cases and controls, whereas in other instances cases may have simply been differentiated from
controls by complications of the disease under
study, such as requirement for AAA surgery. Despite
these limitations, GWAS has led to the identification of some risk alleles of potential value in better
understanding the pathophysiology of AAA. The
most consistent finding has been the association of
SNPs on chromosome 9p21.3 with AAA [32–35]. This
genetic locus was originally identified in a GWAS for
coronary heart disease but has subsequently been
associated with many other vascular and nonvascular
diseases, including AAA and intracranial aneurysms
[32]. The SNPs identified are located far from any
known gene. The best candidate gene in the chromosome 9 region associated with AAA is a noncoding
RNA gene CDKN2BAS, also known as ANRIL. In
mice, a deletion of a 70 kbp region encompassing
rs10757278 (the associated SNP) 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
[36 ]. 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. 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 proinflammatory cytokine interferon via binding of a transcription factor STAT1 [37]. The most
comprehensive study related to the role of 9p21 locus
in AAA found that Cdkn2b knock-out mice subject to
infrarenal aortic elastase infusion develop larger
aortic aneurysms than control mice [38 ]. 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 [38 ]. In a cell culture model, knockdown 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
[38 ]. Another interesting finding was that
CDKN2BAS is able to suppress CDKN2B expression
epigenetically [39]. In conclusion, the current
working hypothesis is that individuals with the risk
allele at the 9p21 locus have lower expression of
CDKN2B that enhances p53-dependent apoptosis
and leads to thinning of the media layer of the aortic
wall, making it more susceptible to dilatation [38 ].
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CHD, coronary heart disease; 95% CI, 95% confidence interval; IA, intracranial aneurysm; OR, odds ratio; PAD, peripheral artery disease; RAF, risk allele frequency in population; SNP, single nucleotide polymorphism.
a
P-values are taken from the first report demonstrating association with AAA.
b
Replicated in multiple populations.
Low density lipoprotein
receptor-related protein 1
(LRP1)
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12q13.3b [42 ]
rs1466535
0.68
1.15 (1.10–1.21)
4.5 1010
CHD, pulmonary embolus, PAD
4.6 1010
1.21 (1.14–1.28)
0.25
DAB2 interacting protein
(DAB2IP)
9q33.1b [41]
rs7025486
Numerous; including CHD, IA, cancers and
Alzheimer’s disease
1.2 1012
0.0028
1.33 (1.10–1.21)
1.31 (1.22–1.42)
0.45
0.42
CDKN2B antisense RNA 1
(CDKN2BAS1)
9p21.3b [32]
rs7635818
Contactin 3 (CNTN3)
3p12.3 [40]
rs10757278
OR (95% CI)
RAF
SNP rs#
Nearest gene (gene symbol)
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Table 1. Genetic loci implicated in AAA and discovered using genome-wide association studies
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Pa
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Genetic locus
These data may provide exciting new translational
research opportunities.
Three GWAS focused on AAA have been published [40,41,42 ]. The first of these studies
employed a DNA pooling strategy to examine 123
cases and 112 screened controls and identified a
genetic locus upstream of the contactin-3 (CNTN3)
gene [40] (Table 1). CNTN3 is a lipid anchored cell
adhesion molecule known to be expressed in the
aortic wall. The finding was replicated in another
502 cases and 296 screened controls. An even stronger association with AAA was observed in a subset of
smokers, who represent the highest risk group for
AAA [40].
In a second AAA GWAS 1292 cases and 30 503
unscreened controls were examined in a discovery
phase in which approximately 300 000 SNPs were
assessed [41]. Three SNPs located in the already
known chromosome 9p21 susceptibility region were
identified to be associated with AAA at genome-wide
significance (P < 1.6 107). In addition, 22 SNPs
were associated with AAA at a P value of less than
5.5 105 and were examined in an independent set
of 3267 cases and 7451 screened controls. One SNP,
rs7025486, within intron 1 of DAB2 interacting
protein (DAB2IP) was associated with AAA and gave
a highly significant P value in combined analyses
with a third set of samples (Table 1). DAP2IP protein
plays a role in suppressing cell survival and proliferation, and is, therefore, a plausible candidate gene
for AAA pathobiology.
In the most recently published GWAS approximately 2000 cases and 5000 unscreened controls
were analyzed [42 ]. Nine loci were associated
with AAA at a P value of less than 1 105 and
assessed for replication in a further sample of 2871
cases and 32 687 controls (mixed group of screened
and unscreened). One SNP, rs1466535, located
within intron 2 of the gene encoding low density
lipoprotein receptor-related protein 1 (LRP1) on
chromosome 12q13.3 was associated with AAA
(Table 1). This finding was confirmed in another
group of 1491 cases and 11 060 unscreened controls. Functional studies suggested that rs1466535
altered expression of the LRP1 gene by modifying
transcriptional regulation of the gene [42 ]. In
support of the importance of LRP1 in aneurysm
formation, mice with inactivation of Lrp1 in vascular smooth muscle cells are prone to aneurysm
formation [43]. LRP1 appears to play a role in
maintaining normal integrity of the blood vessel,
possibly by signaling via Smad, which is also linked
to aneurysm formation via transforming growth
factor b signaling [44].
Overall, these findings demonstrate the power
of using GWAS to identify novel and functionally
Other diseases the locus has been associated with
Genetics of abdominal aortic aneurysm Golledge and Kuivaniemi
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Molecular genetics
relevant mechanisms important in AAA pathogenesis. Future research will include genome-wide
meta-analyses to identify additional genetic risk
factors for AAA.
GENE EXPRESSION STUDIES IN
ABDOMINAL AORTIC ANEURYSM
Microarray-based gene expression has been used to
identify novel biological pathways in the pathogenesis of AAA using aneurysm tissue samples.
These expression data may facilitate functional
studies of genes discovered in genetic association
studies.
An enormous number of studies have assessed
genes or proteins differentially regulated in animal
models or human AAA (see previous reviews [1] and
[45], as well as original articles [46] and [47]). Gene
expression studies have benefitted from technological advances and in particular the development
of microarrays that enable the assessment of relative
expression of the whole genome. Applying this
technology to human AAA is not straightforward
for many reasons [3,45]. Surgical samples from
patients with AAA are becoming less easy to obtain
due to the increasing number of patients treated by
endovascular repair. A particular problem in the
assessment of human AAA samples is what control
samples to use. These difficulties include the problem of matching for age and other risk factors,
which likely effect gene expression, and also the
avoidance of changes that may occur after death
in the case of post-mortem samples. Possibly due to
these technical challenges, currently only four
studies have reported on the use of whole genome
microarrays to assess relative gene expression in
human AAA tissue samples [48,49 ,50] or blood
[51] from AAA patients. In the first of these studies
the gene expression profile was compared in RNA
extracted from biopsies obtained from patients
undergoing AAA repair and controls who underwent post-mortem examination within 24 h of
death. The whole genome expression was compared
in six patients who had AAA and seven controls.
3274 genes were found to be differentially expressed
(1481 unregulated and 1793 downregulated). Many
of the genes identified were related to mechanisms
previously implicated in AAA, including leukocyte
trafficking, T-cell signaling, B-cell signaling, natural
killer cells and other immune mechanisms. Other
upregulated genes and pathways were novel, such as
calcium signaling and MAP kinase pathways, and
this finding was confirmed in a second similar study
by the same investigators [49 ]. Similar immune and
inflammatory pathways were also highlighted in
a microarray study assessing genes differentially
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expressed near the site of rupture within human
AAAs [50].
Microarray-based expression studies also provided evidence that the complement cascade, which
acts at the interface between innate and adaptive
immunity by augmenting antibody responses and
enhancing immunologic memory, plays a role in
the pathobiology of human AAA [52]. Analysis of
microarray data suggests enrichment of activated
components of the complement pathway within
AAA biopsies and also suggests overrepresentation
of binding sites for the transcription factor STAT5A
on the promoter regions of the enriched complement cascade genes, suggesting coordinated regulation of their expression [52]. Another interesting
finding from genome-wide expression studies was
the downregulation of HOX-genes in AAA and their
regional expression along the length of the aorta
[53].
Given the difficulty in obtaining human AAA
samples and suitable control samples, microarrays
have also been used to assess rodent models [54,55],
which could allow a more detailed study of mechanisms since samples at multiple time points and
stages of the disease are available. Two studies used
whole genome microarrays to examine genes differentially expressed within the angiotensin II-induced
apolipoprotein E deficient mouse model of aortic
aneurysms [54,55], and revealed similar pathways
differentially expressed in this model as in human
AAA, supporting the potential value of studying
these models. Further work is needed to determine
mechanisms important in various stages, that is,
initiation, progression and rupture of AAA. Future
work will also include transcriptional genomics to
define mechanisms leading to altered mRNA expression [56]. It is also important to note that human
association studies cannot accredit cause and effect,
as some of the differentially expressed genes most
likely represent a response to the disease rather than
a direct cause.
MICRORNAS AND ABDOMINAL AORTIC
ANEURYSM PATHOGENESIS
Many genetic markers identified in GWAS of complex diseases are at regions distant from known
genes. One possible explanation for the importance
of loci identified within gene deserts is via transcription of noncoding RNAs [57 ]. MicroRNAs
(miRNAs) are a type of noncoding RNA able to
modify gene expression through downregulation
of the expression of multiple genes. There is a growing interest in the role miRNAs could play in disease
pathogenesis and also the therapeutic potential of
modifying miRNAs. A recent study identified five
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Genetics of abdominal aortic aneurysm Golledge and Kuivaniemi
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downregulated miRNAs in human AAA [58 ].
Furthermore, studies in rodent models of AAA
support a role for miRNAs in AAA pathogenesis
and therapy [59 ,60 ]. In one study, inhibition
of miR-29b abrogated AAA expansion in two mouse
models of AAA [59 ]. A similar study by the same
investigators suggested that miR-21 upregulation
inhibited AAA development in the same two mouse
models of AAA and also abrogated the ability of
nicotine to promote AAA [60 ]. These findings
suggest the potential of treatments targeting
miRNAs, although the safety of such therapies in
humans is currently unknown.
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CONCLUSION
Over the last decade there have been exciting new
discoveries in the genetic mechanisms underlying
complex diseases, such as AAA. For example, recent
GWAS results show that SNPs in the 9p21 region,
DAB2IP and LRP1, are associated with human AAA,
and additional data support the validity of these
findings. It is expected that a number of further
important discoveries will be made in the next
few years within this rapidly progressing field.
Efforts to develop electronic phenotyping algorithms could standardize the identification of AAA
cases [61 ]. With decreasing trends in smoking
[62 ,63 ], the epidemiology of AAA is changing
[63 ,64 ], and the importance of genetic risk factors [20 ] is increasing, suggesting that revision of
the current guidelines for AAA screening to target
individuals at increased risk for AAA is needed [6].
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Acknowledgements
Grants from the BUPA and NHMRC (1020955,
1022752, 1021416, 1002707, 1000967) supported this
work. J.G. is supported by a Practitioner Fellowship from
the NHMRC, Australia (1019921) and a Senior Clinical
Research Fellowship from the Queensland Government.
We apologize to those researchers whose important work
we were unable to cite in the room available.
Conflicts of interest
There are no conflicts of interest.
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Molecular genetics
27. Biros E, Norman PE, Jones GT, et al. Meta-analysis of the association between
single nucleotide polymorphisms in TGF-b receptor genes and abdominal
aortic aneurysm. Atherosclerosis 2011; 219:218–223.
This meta-analysis of a number of populations suggested an association between
SNPs in TBFBR2 and AAA, although findings were noted to be disparate in the
different populations examined.
28. Helgadóttir A, Gretarsdottir S, Thorleifsson G, et al. Apolipoprotein(a) genetic
&&
sequence variants associated with systemic atherosclerosis and coronary
atherosclerotic burden but not with venous thromboembolism. J Am Coll
Cardiol 2012; 60:722–729.
This study reports on 35 case–control series that included more than 4500 AAA
patients and found a highly significant association between SNPs in LPA and AAA.
29. Krishna SM, Dear AE, Norman PE, Golledge J. Genetic and epigenetic
mechanisms and their possible role in abdominal aortic aneurysm. Atherosclerosis 2010; 212:16–29.
30. Harrison SC, Holmes MV, Agu O, Humphries SE. Genome wide association
studies of abdominal aortic aneurysms-biological insights and potential
translation applications. Atherosclerosis 2011; 217:47–56.
31. Editorial. Asking for more. Nat Genet 2012; 44:733.
32. Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same sequence
variant on 9p21 associates with myocardial infarction, abdominal aortic
aneurysm and intracranial aneurysm. Nat Genet 2008; 40:217–224.
33. Biros E, Cooper M, Palmer LJ, et al. Association of an allele on chromosome 9
and abdominal aortic aneurysm. Atherosclerosis 2010; 212:539–542.
34. Thompson AR, Golledge J, Cooper JA, et al. Sequence variant on 9p21 is
associated with the presence of abdominal aortic aneurysm disease but does
not have an impact on aneurysmal expansion. Eur J Hum Genet 2009;
17:391–394.
35. Bown MJ, Braund PS, Thompson J, et al. Association between the coronary
artery disease risk locus on chromosome 9p21.3 and abdominal aortic
aneurysm. Circ Cardiovasc Genet 2008; 1:39–42.
36. Visel A, Zhu Y, May D, et al. Targeted deletion of the 9p21 noncoding coronary
&
artery disease risk interval in mice. Nature 2010; 464:409–412.
This is an important study on the potential mechanism of the 9p21 risk allele.
37. Harismendy O, Notani D, Song X, et al. 9p21 DNA variants associated with
coronary artery disease impair interferon-g signalling response. Nature 2011;
470:264–268.
38. Leeper NJ, Raiesdana A, Kojima Y, et al. Loss of CDKN2B promotes p53&&
dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler Thromb Vasc Biol 2013; 33:e1–e10.
The first mechanistic study on the role of the 9p21 risk locus on AAA development
using the elastase-infusion mouse model of AAA.
39. Kotake Y, Nakagawa T, Kitagawa K, et al. Long noncoding RNA ANRIL is
required for the PRC2 recruitment to and silencing of p15(INK4B) tumor
suppressor gene. Oncogene 2011; 30:1956–1962.
40. Elmore JR, Obmann MA, Kuivaniemi H, et al. Identification of a genetic variant
associated with abdominal aortic aneurysms on chromosome 3p12.3 by
genome wide association. J Vasc Surg 2009; 49:1525–1531.
41. Gretarsdottir S, Baas AF, Thorleifsson G, et al. Genome-wide association
study identifies a sequence variant within the DAB2IP gene conferring
susceptibility to abdominal aortic aneurysm. Nat Genet 2010; 42:692–
697.
42. Bown MJ, Jones GT, Harrison SC, et al. Abdominal aortic aneurysm is
&&
associated with a variant in low-density lipoprotein receptor-related protein
1. Am J Hum Genet 2011; 89:619–627.
This large multicenter GWAS in AAA patients identified a risk allele in LRP1.
43. Boucher P, Gotthardt M, Li WP, et al. LRP: role in vascular wall integrity and
protection from atherosclerosis. Science 2003; 300:329–332.
44. Wild JB, Stather PW, Sylvius N, et al. Low density lipoprotein receptor related
protein 1 and abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2012;
44:127–132.
45. Golledge AL, Walker P, Norman PE, Golledge J. A systematic review of
studies examining inflammation associated cytokines in human abdominal
aortic aneurysm samples. Dis Markers 2009; 26:181–188.
46. Koole D, Hurks R, Schoneveld A, et al. Osteoprotegerin is associated with
aneurysm diameter and proteolysis in abdominal aortic aneurysm disease.
Arterioscler Thromb Vasc Biol 2012; 32:1497–1504.
47. Biros E, Walker PJ, Nataatmadja M, et al. Downregulation of transforming
growth factor, beta receptor 2 and Notch signaling pathway in human
abdominal aortic aneurysm. Atherosclerosis 2012; 221:383–386.
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296
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48. Lenk GM, Tromp G, Weinsheimer S, et al. Whole genome expression profiling
reveals a significant role for immune function in human abdominal aortic
aneurysms. BMC Genomics 2007; 8:237.
49. Hinterseher I, Erdman R, Elmore JR, et al. Novel pathways in the pathobiology
&
of human abdominal aortic aneurysms. Pathobiology 2013; 80:1–10.
In this study a custom array was designed to measure mRNA levels for 43 genes.
Follow-up studies included immunohistological analyses of 10 proteins.
50. Choke E, Cockerill GW, Laing K, et al. Whole genome-expression profiling
reveals a role for immune and inflammatory response in abdominal aortic
aneurysm rupture. Eur J Vasc Endovasc Surg 2009; 37:305–310.
51. Giusti B, Rossi L, Lapini I, et al. Gene expression profiling of peripheral blood
in patients with abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2009;
38:104–112.
52. Hinterseher I, Erdman R, Donoso LA, et al. Role of complement cascade in
abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2011; 31:1653–
1660.
53. Lillvis JH, Erdman R, Schworer CM, et al. Regional expression of HOXA4
along the aorta and its potential role in human abdominal aortic aneurysms.
BMC Physiol 2011; 11:9.
54. Rush C, Nyara M, Moxon JV, et al. Whole genome expression analysis within
the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic
aneurysm. BMC Genomics 2009; 10:298.
55. Spin JM, Hsu M, Azuma J, et al. Transcriptional profiling and network analysis
of the murine angiotensin II-induced abdominal aortic aneurysm. Physiol
Genomics 2011; 43:993–1003.
56. Nischan J, Gatalica Z, Curtis M, et al. Binding sites for ETS family of transcription
factors dominate the promoter regions of differentially expressed genes in
abdominal aortic aneurysms. Circ Cardiovasc Genet 2009; 2:565–572.
57. Gamazon ER, Ziliak D, Im HK, et al. Genetic architecture of microRNA
&&
expression: implications for the transcriptome and complex traits. Am J
Hum Genet 2012; 90:1046–1063.
The study investigated the relationship between genetic variation, miRNA expression, and mRNA expression. Genome-wide expression profiling of lymphoblastoid
cell lines identified hundreds of miRNAs whose increased expression correlated
with correspondingly reduced expression of target mRNAs.
58. Pahl MC, Derr K, Gäbel G, et al. MicroRNA expression signature in human
&
abdominal aortic aneurysms. BMC Med Genomics 2012; 5:25.
This study is the first study measuring microRNA levels in human AAA and
identified and validated five downregulated microRNAs.
59. Maegdefessel L, Azuma J, Toh R, et al. Inhibition of microRNA-29b reduces
&&
murine abdominal aortic aneurysm development. J Clin Invest 2012; 122:
497–506.
Using two animal models of aortic aneurysms, this study suggested that inhibiting
one miRNA could stabilize aneurysms.
60. Maegdefessel L, Azuma J, Toh R, et al. MicroRNA-21 blocks abdominal aortic
&&
aneurysm development and nicotine-augmented expansion. Sci Transl Med
2012; 4:122ra22.
Using two animal models of aortic aneurysms, this study suggested that upregulating one miRNA could stabilize aneurysms.
61. Kho AN, Pacheco JA, Peissig PL, et al. Electronic medical records for genetic
&&
research: Results of the eMERGE consortium. Sci Translat Med 2011;
3:79re1.
The electronic MEdical Records and GEnomics (eMERGE) network is developing
phenotyping algorithms to standardize identification of cases for genetic studies.
AAA is one of the phenotypes under investigation.
62. Svensjö S, Björck M, Gurtelschmid M, et al. Low prevalence of abdominal
&&
aortic aneurysm among 65-year-old Swedish men indicates a change in the
epidemiology of the disease. Circulation 2011; 124:1118–1123.
This population-based screening study of 65-year-old men carried out in Sweden
found lower than expected prevalence of AAA, an unchanged AAA repair rate, and
a significantly improved longevity of the elderly population.
63. Lederle FA. The rise and fall of abdominal aortic aneurysm. Circulation 2011;
&&
124:1097–1099.
This is an insightful editorial on the trends of AAA prevalence.
64. Choke E, Vijaynagar B, Thompson J, et al. Changing epidemiology of
&&
abdominal aortic aneurysms in England and Wales: older and more benign?
Circulation 2012; 125:1617–1625.
The study shows overall decline in AAA incidence, prevalence and mortality, but no
change in the admissions for unruptured AAAs and 17% increase in the number of
repair operations from 2001 to 2009.
Volume 28 Number 3 May 2013