Genetics of Abdominal Aortic Aneurysms

Aneurysms of the abdominal aorta (AAA) develop frequently in smoking, elderly
males. Rupture of an AAA has a mortality rate of 85%. Therefore, AAAs are
considered for surgery when they exceed the 55 mm diameter threshold that marks
the borderline from which on the risk of rupture is superior to the mortality
risk of surgery. There are 2 surgical options for an AAA, the conventional open
repair and the endovascular treatment. The Dutch Randomised Endovascular
Aneurysm Management (DREAM) trial was recently initiated in order to determine
which procedure is superior. However, AAAs are usually asymptomatic and are
therefore often not diagnosed. Randomised trials have indicated that ultrasound
screening is effective in reducing AAA-related mortality, but before this
screening is implemented in the clinical routine a high-risk population needs
to be defined in detail. A family history of AAAs is the main risk factor for
AAA development, with odds ratios varying from 4.1 to 9.7. In 3 Dutch families,
with 4 or 5 affected siblings, a locus on chromosome 19q13.3 was described with
a logarithm of odds (LOD) score of 3.95. This region contains approximately 250
genes. Based on the pathophysiology of AAAs, disease associated genes can
encode inflammatory, immune, and extracellular matrix related proteins. We were
therefore able to reduce the 250 genes of the 19q13.3 region to 12 functional
candidate genes, and we aim to test the tagging SNPs of these genes to cover
all the underlying genetic variation.
Additionally, genome wide association studies can scan the entire genome for
SNPs that predispose to AAA formation.
The effects of the genetic variants can be studied in the RNA by investigating
differences in expression levels or splicing between AAA cases and controls.

To identify an AAA associated genes by a functional candidate gene approach.

The identification of an AAA associated gene will have several impacts on this
high prevalent disease:
1. It will improve our understanding of the molecular pathways involved in the
development of AAAs. The processes that induce and promote AAA formation, like
extracellular matrix reduction, inflammatory and immune responses, are well
known. However, the main molecular players in these events are still elusive.
Finding AAA predisposing SNPs in a certain gene will reveal the involvement of
the encoded protein. Future studies, like transcription profiling and
functional assays, may then further elucidate the molecular mechanisms.
2. It will allow defining a high risk group, which offers the possibility to:
a. perform more effective screening strategies
b. design prevention therapies for this group, that are based on the improved
knowledge of the molecular mechanisms involved in the development of AAAs.

3. To study the effects of genetic variants on RNA level.

1. Compare genetic profile of 650 AAA patients with that of 650 healthy age-sex
matched controls. Specifically, tagging SNPs of candidate genes in the 19q13.3
region will be tested.

2. We will generate Genome wide association data of 1000 AAA patients and
compare this to the genotype data of 2000 controls (from the NBS), The most
promising SNPs will be tested in an additional cohort of 500 AAA pateints and
1000 controls.

3. We will study the effects of genetic variants on RNA level by comparing
expression levels and splicing between cases and controls. RNA of at least 100
control samples is available in our laboratory.

Minimal burden and risk, once blood withdrawel (30 ml)