Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms.

Intracranial aneurysm is probably a complex disease with both genetic and non-genetic or environmental risk factors contributing to the etiology of the disease. A disruption of the extracellular matrix (ECM) of the arterial wall is a likely factor in the pathogenesis of intracranial aneurysms. We analyzed 44 potential candidate genes involved in the maintenance of the integrity of the ECM in 382 Dutch Caucasian patients with intracranial aneurysms and 609 Dutch Caucasian controls for 384 tag single nucleotide polymorphisms (SNPs) using the GoldenGate assay on an Illumina BeadStation 500 GX. We identified SNPs that were associated with intracranial aneurysms (P<0.01) in six of these 44 genes: serpine1 (SERPINE1, P=0.0008), transforming growth factor beta induced (TGFBI, P=0.0026), perlecan (HSPG2, P=0.0044), fibronectin (FN1, P=0.0069), fibrillin 2 (FBN2, P=0.0077) and alpha 1 type IV collagen (COL4A1, P=0.0087). In a second independent cohort of 310 Dutch Caucasian intracranial aneurysm patients and 336 Dutch Caucasian controls, the association for the HSPG2 gene [combined odds ratio (OR) 1.33, 95% confidence interval (CI) 1.13-1.57, P=6 x 10(-4)] was replicated. The population attributable risk (PAR) for this SNP is 19%. Combining the two cohorts still showed association for the SERPINE1 (combined OR 1.27, 95% CI 1.07-1.50, P=0.004, PAR 6%), FBN2 (combined OR 1.37, 95% CI 1.07-1.75, P=0.01, PAR 3%) and COL4A1 (combined OR 1.22, 95% CI 1.05-1.42, P=0.007, PAR 7%) genes. These PARs are likely to be overestimates as they are calculated from the joint analyses combining stages 1 and 2 of our association study. Our findings indicate that variation in genes involved in the maintenance of the integrity of the ECM of the arterial wall plays a role in susceptibility to intracranial aneurysms. These findings further support our hypothesis that diminished maintenance of the ECM of the arterial wall is important in the development of intracranial aneurysms.