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Contributors
xiii
Gautam Agarwal, MD
Department of Cardiothoracic and Vascular Surgery, Medical College
of Georgia, Augusta, GA
B. Timothy Baxter, MD
Department of Surgery, University of Nebraska Medical Center
and Methodist Hospital, Omaha, NE
W.T.G.J. Bos, MD
Department of Surgery, University Medical Center Groningen, Groningen,
The Netherlands
Martin J. Carignan, M.D
Section of Vascular Surgery and Endovascular Therapy, University
of Alabama at Birmingham, Birmingham, AL
Timothy A.M. Chuter, D.M.
Department of Surgery, Division of Vascular Surgery, University of
California-San Francisco, San Francisco, CA
Enrique Criado, MD
Department of Surgery, Division of Vascular Surgery, University
of Michigan Health System, Ann Arbor, MI
Alan Dardik, MD, PhD
Department of Surgery, Division of Vascular Surgery, Yale University School
of Medicine, New Haven, CT
K. Barry Deatrick, MD
Department of Surgery, Section of Vascular Surgery, University of Michigan
Health System, Ann Arbor, MI
G. Michael Deeb MD
Department of Surgery, Division of Cardiac Surgery, University of Michigan
Cardiovascular Center, Ann Arbor, MI
Manuel Doblas, MD
Division of Vascular Surgery, Centro Hospitalario Virgen de la Salud,
Toledo, Spain
https://t.me/med1917
xiv Contributors
J.J.A.M. van den Dungen, MD
Department of Surgery, University Medical Center Groningen, Groningen,
The Netherlands
Jonathan L. Eliason, MD
Department of Surgery, Section of Vascular Surgery, University of Michigan
Health Systems, Ann Arbor, MI
Michael J. Englesbe, MD
Department of Surgery, Division of Transplantation, University of Michigan
Health System, Ann Arbor, MI
Guillermo A. Escobar, MD
Department of Surgery, University of Colorado Health Science Center and
Denver Health Medical Center, Denver, CO
Mark A. Farber, MD
Department of Surgery, Division of Vascular Surgery, University of North
Carolina School of Medicine, Chapel Hill, NC
Tamara N Fitzgerald, MD
Department of Surgery, Yale University School of Medicine, New Haven, CT
Angel Flores, MD
Division of Vascular Surgery, Centro Hospitalario Virgen de la Salud,
Toledo, Spain
Juan Fontcuberta, MD
Division of Vascular Surgery, Centro Hospitalario Virgen de la Salud,
Toledo, Spain
Peter Ford, M.B.B.S
Department of Surgery, Division of Vascular Surgery, University of North
Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
Thomas R Gest, MD
Department of Anatomical Sciences and Medical Education, University
of Michigan Health System, Ann Arbor, MI
Jose Gil, MD
Division of Vascular Surgery, Centro Hospitalario Virgen de la Salud,
Toledo, Spain
Peter K. Henke, MD
Department of Surgery, Section of Vascular Surgery, Cardiovascular Center,
University of Michigan Health System, Ann Arbor, MI
Loay S. Kabbani M.D
Department of Surgery, Section of Vascular Surgery, University of Michigan
Medical Center, Ann Arbor, MI
Paul Knechtges, MD
Department of Radiology, University of Michigan Health System,
Ann Arbor, MI
Brian S. Knipp, MD
Department of Surgery, Section of Vascular Surgery, University of Michigan
Health System, Ann Arbor, MI
https://t.me/med1917
Contributors xv
Venkataramu N. Krishnamurthy, MD
Department of Radiology, Section of Interventional Radiology, University
of Michigan, Ann Arbor, MI.
Helena Kuivaniemi, MD, PhD
Center for Molecular Medicine and Genetics, Department of Surgery, Wayne
State University School of Medicine, Detroit, MI, USA
Ignacio Leal, MD
Division of Vascular Surgery, Centro Hospitalario Virgen de la Salud,
Toledo, Spain
Guy M. Lenk, PhD
Center for Molecular Medicine and Genetics, Wayne State University School
of Medicine, Detroit, MI
John H. Lillvis, BA
Center for Molecular Medicine and Genetics, Wayne State University School
of Medicine, Detroit, MI
Peter S. Liu, MD
Department of Radiology, Division of Magnetic Resonance Imaging,
University of Michigan Medical Center, Ann Arbor, MI
William A. Marston, MD
Department of Surgery, Division of Vascular Surgery, University of North
Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
Robert Mendes, M.D
Department of Surgery, Division of Vascular Surgery, University of North
Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
J. Gregory Modrall, M.D.
Department of Surgery, Division of Vascular and Endovascular Surgery,
University of Texas Southwestern Medical Center,
Dallas, TX
Bart E Muhs, MD, PhD
Co-Director, Endovascular Program, Yale University School of Medicine,
New Haven, CT
Patrick J. O’Hara, M.D.
Department of Vascular Surgery, Cleveland Clinic Lerner College of
Medicine of Case Western Reserve University, Cleveland Clinic Foundation,
Cleveland, OH
Antonio Orgaz, MD
Division of Vascular Surgery, Centro Hospitalario Virgen de la Salud,
Toledo, Spain
Juan C. Parodi, MD
Department of Vascular Surgery, University of Miami Leonard M. Miller
School of Medicine, Miami, FL
Marc A. Passman, M.D
Section of Vascular Surgery and Endovascular Therapy, University
of Alabama at Birmingham, Birmingham, AL
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xvi Contributors
Himanshu J. Patel MD
Department of Surgery, Section of Cardiac Surgery, University of Michigan
Cardiovascular Center, Ann Arbor, MI
Sheela T. Patel, MD
Department of Surgery, University of Miami Leonard M. Miller School
of Medicine, Miami, FL
William H. Pearce, M.D
Department of Surgery, Division of Vascular Surgery, Feinberg School
of Medicine, Northwestern University, Chicago, IL
T.R. Prins, MD
Departments of Surgery and Radiology, University Medical Center
Groningen, Groningen, The Netherlands
Kerianne H. Quanstrum, M.D
Department of Surgery, University of Michigan Health System
Cardiovascular Center, Ann Arbor, MI
Todd E. Rasmussen, MD
San Antonio Military Vascular Surgery Service, United States Air Force
Medical Center, San Antonio, TX
John E. Rectenwald, MD
Department of Surgery and Radiology, Sections of Vascular Surgery
and Interventional Radiology, University of Michigan, Ann Arbor, MI.
Paul J. Riesenman, MD, MS
Department of Surgery, Division of Vascular Surgery, University of North
Carolina School of Medicine, Chapel Hill, NC
Vera P. Shively, M.S
Department of Surgery, Division of Vascular Surgery, Feinberg School
of Medicine, Northwestern University, Chicago, IL
Gregorio Sicard, MD
Department of Surgery, Section of Vascular Surgery, Washington University
School of Medicine, St. Louis, MO
Matthew J. Sideman, M.D.
Department of Surgery, Section of Vascular and Endovascular Surgery,
Oklahoma University College of Medicine, Tulsa, OK
A.O. Sondakh, MD
Department of Surgery, University Medical Center Groningen, Groningen,
The Netherlands
James C. Stanley, MD
Department of Surgery, Section of Vascular Surgery, University of Michigan
Cardiovascular Center, Ann Arbor, MI
Houman Tamaddon, M.D.
Department of Surgery, Division of Vascular Surgery, University of North
Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
https://t.me/med1917
Contributors xvii
Kevin E. Taubman, M.D.
Department of Surgery, Section of Vascular and Endovascular Surgery,
Oklahoma University College of Medicine, Tulsa. OK
I.F.J. Tielliu, MD
Department of Surgery, University Medical Center Groningen, Groningen,
The Netherlands
Gilbert R. Upchurch, Jr. M.D.
Department of Surgery, Section of Vascular Surgery, University of Michigan
Medical Center, Ann Arbor, MI
E.L.G. Verhoeven, MD
Department of Surgery, University Medical Center Groningen, Groningen,
The Netherlands
Thomas Wakefield, MD
Department of Surgery,, Section of Vascular Surgery, University of Michigan
Health System, Ann Arbor, MI
Michael Wilderman
David M. Williams, MD
Department of Radiology, Division of Vascular and Interventional Radiology,
University of Michigan Medical Center, Ann Arbor, MI
C.J. Zeebregts, MD
Department of Surgery, University Medical Center Groningen, Groningen,
The Netherlands
https://t.me/med1917
Abstract Abdominal aortic aneurysm (AAA) is a multifactorial disease with
a significant genetic component. Epidemiological studies have identified fam-
ily history of AAA as a risk factor for both aneurysm development and rupture,
making it an important consideration for targeted ultrasound screening of eld-
erly patients and their family members. Ongoing research into the genetics of
AAA is focused on identifying risk factor genes for both familial and sporadic
aneurysms through the use of linkage analyses and genetic association studies,
although no causative mutations have yet been identified. Additionally, micro-
array expression profiling and animal models of aneurysms are being used
to identify genes and pathways for the design of novel therapeutics. These
approaches promise to deliver a better understanding of aneurysms at the mo-
lecular level leading to improved screening and treatment.
Keywords DNA linkage , Genetic association , Chromosome 19 , Chromosome 4 ,
Animal models , Family studies , Ultrasonography screening , Microarray
Introduction
Abdominal aortic aneurysms (AAAs) contribute significantly to the disease burden
of the elderly population, with as much as 10% of the population over the age of
65 harboring an aneurysm.
1
Between 1999 and 2004, AAA was the 17th leading
cause of death in the United States, with approximately 15,000 deaths per year.
2
Advances in screening and endovascular surgical techniques have contributed to
modest decreases in AAA mortality, but further developments are still necessary.
The current treatment of choice, elective surgical repair, is highly effective when
performed, with a mortality of less than 5% as compared with up to a 90% mortality
associated with rupture.
3,
4
However, since most AAAs do not produce symptoms
until rupture, early detection is necessary for effective therapy. Additionally, due to
age or comorbidities, some patients may not be appropriate candidates for surgery.
Improvements in detection and therapy are therefore necessary to identify and treat
aneurysms prior to their growth and rupture. One promising area of research that
may lead to such developments is the study of AAA genetics.
Chapter 1
Genetics of Abdominal Aortic
Aneurysms
John H. Lillvis , Guy M. Lenk, and Helena Kuivaniemi
G. Upchurch and E. Criado (eds.) Aortic Aneurysms, Contemporary Cardiology
DOI: 10.1007/978-1-60327-204-9_1, © Humana Press, a part of
Springer Science + Business Media, LLC 2009
1
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2 J.H. Lillvis et al.
There is strong evidence to suggest a genetic component to AAA. AAAs
frequently show familial clustering, even when they are not associated with
heritable disorders, such as the Marfan syndrome or the type IV variant of
the Ehlers-Danlos syndrome. In an examination of over 125,000 Veterans
Administration patients, Lederle et al.
5
found family history of AAA to be
one of the best predictors of aneurysms, with an odds ratio of 1.93 (95% con-
fidence intervals: 1.71–2.18) for small aneurysms and 1.94 (95% confidence
intervals: 1.63–2.32) for large aneurysms, with only smoking being a stronger
risk factor. Interviews with AAA patients and ultrasonography examinations
of their first-degree relatives have shown that approximately 15% have at least
one first-degree relative with the disease
6–
9
(Tables 1 and 2 ). Examination of
952 brothers and 771 sisters of AAA patients by ultrasonography showed that
19.5% of brothers and 5.7% of sisters had AAA
22–
25,
27–
30,
32–
34,
36–
38
(Table 2 ).
In addition, AAA exhibits many characteristics consistent with being a genetic
disease. Segregation analysis, a statistical approach to examine heredity, has
been used to study cases of AAA in two populations.
16,
17
One study suggested
a dominant and the other a recessive mode of inheritance for AAA, possibly
representing genetic heterogeneity, but each study concluded that a single gene
defect is likely to cause the disease within a family. In addition to the formal
statistical analyses supporting the genetic nature of AAA, several collections
of AAA families have been reported, the largest one describing 233 families
with multiple affecteds.
39
AAA also demonstrates characteristics of being a multifactorial genetic
disease with respect to gender. One feature of multifactorial diseases is
gender discrepancy in prevalence, a phenomenon that is well documented
in diseases such as pyloric stenosis, many congenital heart defects, neural
tube defects, and cleft lip.
40
For AAA, the prevalence is about six times
higher in males than females, perhaps due to hormonal protection in females.
However, when females do present with an aneurysm, it would presumably
be due to having a greater genetic or environmental liability and would
therefore represent the more severe end of the spectrum of disease.
41
This
Table 1 Familial prevalence of AAA based on interviews.
Study Patients surveyed (N)
Patients with posi-
tive history ( N ) Familial prevalence (%)
Norrgård et al., 1984
10
87 16 18.4
Johansen and Koepsell, 1986
11
250 48 19.2
Powell and Greenhalgh, 1987
12
56 20 35.7
Johnston and Scobie, 1988
13
666 41 6.1
Cole et al., 1989
14
305 34 11.1
Darling et al., 1989
15
542 82 15.1
Majumder et al., 1991
16
91 13 14.3
Verloes et al., 1995
17
313 39 12.5
Lederle et al., 1997
18
985 91 9.2
Lawrence et al., 1998
19
86 19 22.1
Salkowski et al., 1999
20
72 19 26.4
Rossaak et al., 2001
21
248 48 19.4
Total 3701 470
Combined prevalence 12.7
Modified with permission from Kuivaniemi and Tromp
9
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Chapter 1 Genetics of Abdominal Aortic Aneurysms 3
is supported by the fact that females have an increased operative mortality
for both intact and ruptured AAAs compared to males.
42,
43
Additionally, if
the liability is genetic, one would expect to see a higher prevalence among
females inheriting the mutations. In one study of 542 AAA patients, the 82
(15.1%) patients who had a positive family history were compared to the 460
sporadic cases.
15
When examined for gender distribution, the sporadic cases
showed an expected 86%:14% male-to-female ratio, whereas 35% of the
familial cases were female, despite no differences in smoking, hypertension,
or coronary artery disease. An investigation of rupture rates of the patients
with a positive family history, as well as their first-degree relatives, found that
22/73 (30.1%) aneurysms in females ruptured as compared to 23/136 (16.9%)
in males. Finally, it was also found that the males with a family history were
significantly younger than the males with sporadic aneurysms, another char-
acteristic consistent with genetic diseases. Similar results were reported in
a different study of 300 AAA patients that showed a higher rate of rupture
among familial cases of AAA.
44
Based on the research described above, it is clear that AAA is a complex
multifactorial disease with genetic and environmental risk factors (Fig. 1 ).
Because of technological and statistical advances in the past several years,
studying the genetics of multifactorial diseases like AAA has become quite
feasible. Figure 2 shows the so-called “four pillars” for the study of AAA
genetics. These four approaches can each provide valuable information as well
as complement each other to help unlock the genetics of AAA.
Table 2 Prevalence of AAA among first-degree family members based on ultrasonogra-
phy screening.
Study Country Brothers
a
(%) Sisters
a
(%) Other
a
(%)
Bengtsson et al., 1989
22
Sweden 10/35 (28.6) 3/52 (5.8)
Collin and Walton, 1989
23
UK 4/16 (25.0) 0/15 (0)
Webster et al., 1991
24
USA 5/24 (20.8) 2/30 (6.7) 7/103 (6.8)
Adamson et al., 1992
25
UK 5/25 (20.0) 3/28 (10.7)
Bengtsson et al., 1992
26
Sweden 9/62
van der Lugt et al., 1992
27
The Netherlands 16/56 (28.6) 3/52 (5.8)
Adams et al., 1993
28
UK 4/23 (17.4) 1/28 (3.6) 6/23 (26.1)
Moher et al., 1994
29
Canada 9/48 (18.8)
Fitzgerald et al., 1995
30
Ireland 13/60 (21.7) 2/65 (3.1)
Larcos et al., 1995
31
Australia 0/52 (0)
Baird et al., 1995
32
Canada 7/26 (26.9) 3/28 10.7)
Jaakkola et al., 1996
33
Finland 4/45 (8.9) 1/78 (1.3)
van der Graaf et al., 1998
34
Netherlands 26/210 (12.4)
Salo et al., 1999
35
Finland 11/238 (4.6)
Rossaak et al., 2001
21
New Zealand 4/49 (8.2)
Frydman et al., 2003
36
Australia 64/150 (42.7) 20/126 (15.9)
Ogata et al., 2005
37
Canada 11/98 (11.2) 4/147 (2.7) 0/31 (0)
Badger et al., 2007
38
Northern Ireland 8/136 (5.8) 2/122 (1.6) 0/42 (0)
Total 186/952 (19.5) 44/771 (5.7) 37/638 (5.7)
a
Number of individuals identified with AAA/number of individuals examined by ultrasonography. Other refers
to relatives other than sisters and brothers of the AAA patient, or the categories of relatives were not specified.
Modified with permission from Kuivaniemi and Tromp
9
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4 J.H. Lillvis et al.
Clinical Management and the Genetics of AAA
Despite the strong evidence for a genetic component to AAA, clinical recogni-
tion of this aspect is still largely lacking. Nakka et al. identified poor documen-
tation concerning the counseling of patients on the occasional familial nature
of AAA.
45
Additionally, “Practical Genetic Counseling”, a commonly used
genetic counseling reference, only describes familial aneurysms due to type
III collagen defects.
46
The primary clinical implication of understanding AAAs as a genetic dis-
ease is targeted screening with imaging techniques. In addition to being a risk
factor for developing an aneurysm, family history has been shown in both
Fig. 1 Abdominal aortic aneurysm ( AAA ) pathogenesis with associated risk factors. Risk factors ( above the
arrows ) contributing to and biological processes ( below the arrows ) observed in AAA formation, growth, and
rupture are summarized. How AAAs form, grow, and rupture is not fully understood, but it is clear that AAA is
a complex disease with both genetic and environmental risk factors. Many of the same risk factors and processes
are involved in initiation and progression as well as rupture. ECM , extracellular matrix .
Fig. 2 Four pillars of abdominal aortic aneurysm ( AAA ) research. Unraveling the
pathophysiology of AAA and identifying the specific risk factors for AAA will require
interdisciplinary approaches. Each approach is described in the text and specific exam-
ples on how they are applied to AAA research are also presented.
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Chapter 1 Genetics of Abdominal Aortic Aneurysms 5
epidemiological and aortic modeling studies to be a risk factor for aneurysm
rupture.
47,
48
Currently, the screening guidelines for AAA are conflicted as
to whether family history should be included in the criteria for targeted
screening. The US Preventive Task Force recommends screening only men
between the ages of 65 and 75 who have smoked, citing concerns over psy-
chological harm and early treatment. However, the guidelines acknowledge
that screening can be considered in patients with a strong family history of the
disease.
49,
50
In contrast, the Society for Vascular Surgery and the Society for
Vascular Medicine and Biology recommend screening all patients over the age
of 50 with a family history of aneurysms.
51
In a study of familial aneurysms,
Le Hello et al. similarly recommend screening of all patients with two or more
affected relatives.
52
Since a positive family history can vary from multiple
siblings or parents of both genders to a single brother who smoked, targeted
screening based upon family history should rely on a careful patient interview
and clinical judgment. Additionally, referral to a genetic counselor or medical
genetics specialist may be useful if the patient exhibits a particularly strong
family history of aneurysms.
In the future, the clinical management of AAA may be fundamentally altered
by an improved understanding of the genetics of the disease. Identification of
risk alleles will help identify individuals more likely to develop the disease.
Additionally, targeted therapeutics may be developed as new genes and path-
ways important to the development of AAA are found.
Identification of AAA-Susceptibility Loci by Genome-Wide
DNA Linkage Analyses
Linkage is a genetic concept referring to the coinheritance of a polymorphic
DNA marker, a variation in the DNA sequence, with a DNA mutation confer-
ring susceptibility for a phenotype or disease.
53
Linkage indicates that the
marker is in proximity to the causative mutation since the distance between
two points on a chromosome is proportional to the frequency of crossing over.
The use of linkage analysis to identify the genetic causes of lethal, late-age-at-
onset diseases, such as AAA, has been difficult at best and has required several
technological advancements to make the undertaking of such studies a real-
ity. First, the use of noninvasive diagnostic imaging, such as ultrasonography
screening studies carried out on the relatives of AAA patients, has allowed
the identification of far more family members with AAA prior to rupture
(Table 2 ). As a result, there are far more living, affected members available
for genetic studies. Second, the development of highly informative markers
that can be easily analyzed using PCR has greatly enhanced the power of any
linkage study. Third, the large number of linkage studies being performed on
complex human diseases has refined and advanced the methods and models
for linkage analyses. Fourth, there have been theoretical and applied advances
in the linkage methodology itself.
53
Recently, two published reports identified genetic loci linked to AAA using a
method of DNA linkage analysis known as the sib-pair approach.
54,
55
By relying
upon a feature of sibling relationships, namely the sharing of 0, 1, or 2 identical
alleles at any genetic locus, the distribution of alleles expected by chance can be
easily predicted. Although sibling pairs are perhaps the most commonly used,
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