Introduction:
Intracranial aneurysms affect 2-5% of the general population.1 A tiny proportion of these
rupture leading to aneurysmal subarachnoid haemorrhage (SAH), which can be fatal instantly
or lead to life-changing neurological morbidity in a young group of stroke survivors.
Understanding the pathophysiological mechanisms underlying intracranial aneurysms, and
being able to predict which patients have a higher risk of rupture has led to intensive research
efforts, via epidemiological, molecular and genetic studies. Our aim was to determine the
association of candidate genes with intracranial aneurysms in a large UK Caucasian population.
Methods:
We performed a case-control genetic association study of single nucleotide polymorphisms
(SNPs) in over 1600 patients with intracranial aneurysms from a UK-wide Genetic and
Observational Subarachnoid Haemorrhage (GOSH) study and 1500 controls from the
Wellcome cohort,2 utilising a candidate-gene approach. We conducted a literature review and
performed a meta-analysis of the existing candidate gene studies to better determine which
genes would be suitable for analysis in our cohort. We also performed a new meta-analysis
using our data for each SNP examined to determine if our genetic associations with intracranial
aneurysms were robust.
Results:
We examined 22 SNPs related to vascular endothelial integrity, the extracellular matrix, and
inflammation. Two SNPs showed associations with intracranial aneurysms in our UK cohort:
the D allele of ACE Insertion/Deletion SNP (associated with vascular endothelial function; OR
1.14 [1.02-1.28], p=0.02) and the MMP-2 C>T rs243865 SNP (associated with extracellular
matrix integrity; OR 1.18 [1.04 – 1.33], p=0.012).
Conclusions:
We found associations with intracranial aneurysms for the D allele of the ACE I/D SNP, and a
potentially functionally significant MMP-2 SNP. Both genes have plausible connections to IA
pathophysiology (endothelial function and extracellular matrix integrity, respectively), and
could potentially predispose patient to aneurysm rupture as demonstrated by sub-group
analysis.