Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival.
Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance.
About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening.
This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population.
AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis.
It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway.
Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024).
A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA.
Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006.
The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms.
Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined.
From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.
| Identifer | oai:union.ndltd.org:ADTP/217528 |
| Date | January 2004 |
| Creators | Rossaak, Jeremy Ian, n/a |
| Publisher | University of Otago. Dunedin School of Medicine |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Jeremy Ian Rossaak |
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