title: Gene expression profiling reveals distinct molecular signatures associated with the rupture of intracranial aneurysm.
abstract: OBJECTIVE
  The rupture of intracranial aneurysm (IA) causes subarachnoid hemorrhage associated with high morbidity and mortality. We compared gene expression profiles in aneurysmal domes between unruptured IAs and ruptured IAs (RIAs) to elucidate biological mechanisms predisposing to the rupture of IA.
  
  
  METHODS
  We determined gene expression levels of 8 RIAs, 5 unruptured IAs, and 10 superficial temporal arteries with the Agilent microarrays. To explore biological heterogeneity of IAs, we classified the samples into subgroups showing similar gene expression patterns, using clustering methods.
  
  
  RESULTS
  The clustering analysis identified 4 groups: superficial temporal arteries and unruptured IAs were aggregated into their own clusters, whereas RIAs segregated into 2 distinct subgroups (early and late RIAs). Comparing gene expression levels between early RIAs and unruptured IAs, we identified 430 upregulated and 617 downregulated genes in early RIAs. The upregulated genes were associated with inflammatory and immune responses and phagocytosis including S100/calgranulin genes (S100A8, S100A9, and S100A12). The downregulated genes suggest mechanical weakness of aneurysm walls. The expressions of Krüppel-like family of transcription factors (KLF2, KLF12, and KLF15), which were anti-inflammatory regulators, and CDKN2A, which was located on chromosome 9p21 that was the most consistently replicated locus in genome-wide association studies of IA, were also downregulated.
  
  
  CONCLUSIONS
  We demonstrate that gene expression patterns of RIAs were different according to the age of patients. The results suggest that macrophage-mediated inflammation is a key biological pathway for IA rupture. The identified genes can be good candidates for molecular markers of rupture-prone IAs and therapeutic targets.
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.).
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakaoka
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.).
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.).
authors.forename: Taku
authors.initials: T
authors.lastname: Yoneyama
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.).
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hosomichi
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.).
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kasuya
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.).
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: From the Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan (H.N., K.H., I.I.); Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (A.T.); Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (T.Y., H.K.); and Department of Neurosurgery, School of Medicine, Showa University, Tokyo, Japan (T.M.). itinoue@nig.ac.jp.
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017542:Aneurysm, Ruptured / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D012307:Risk Factors; D013699:Temporal Arteries / Q000378:metabolism*
keywords: gene expression; inflammation; intracranial aneurysm; macrophages; microarray analysis; rupture; subarachnoid hemorrhage