Background and Purpose-Mechanisms underlying development and rupture of intracranial aneurysms (IA) are poorly recognized. The majority of studies on human tissue have focused on predefined pathways. We sought to analyze global gene expression patterns of ruptured IA, unruptured IA, and control vessels. Methods-Transcription profiles were studied in human ruptured (nϭ8) and unruptured (nϭ6) IA, as well as in control intracranial arteries (nϭ5), using oligonucleotide microarrays. Real-time reverse-transcription polymerase chain reaction was used for confirmation. Functional analysis for determination of over-represented ontological groups among gene expression profiles was also performed. Results-The expression of 159 genes differed among the studied groups. Compared to the controls, 131 genes showed common directions of change in both IA groups. The most impacted biological processes for IA are: (1) the muscle system; (2) cell adhesion (downregulation); and (3) the immune system and inflammatory response (upregulation). Ruptured and unruptured IA differed in genes involved in immune/inflammatory processes; expression was reduced in ruptured IA. Conclusions-Decreased expression of genes related to muscle system and cell adhesion is important for the development of IA.
Background and Purpose Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. Methods Initial analysis was performed in a discovery sample of 2,617 IA cases and 2,548 controls of Caucasian ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in two independent replication samples: Dutch (717 cases; 3,004 controls) and Finnish (799 cases; 2,317 controls). A meta-analysis was performed to combine the results from the three studies for key chromosomal regions of interest. Results Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: p< 1.0 × 10−11), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; p= 4.14 × 10−8). This association replicated in the Dutch sample (p=0.01), but failed to show association in the Finnish sample (p=0.25). Meta-analysis results of the three cohorts reached statistical significant (p=9.91 × 10−10). Conclusions We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.
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