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.).
Stroke. 2014 Aug;45(8):2239-45. doi: 10.1161/STROKEAHA.114.005851. Epub 2014 Jun 17.
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.
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.
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.
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.
颅内动脉瘤（IA）的破裂会导致蛛网膜下腔出血，伴有高发病率和死亡率。我们比较了未破裂的 IA 和破裂的 IA（RIA）之间的动脉瘤穹顶的基因表达谱，以阐明导致 IA 破裂的生物学机制。
我们使用 Agilent 微阵列确定了 8 个 RIA、5 个未破裂的 IA 和 10 个颞浅动脉的基因表达水平。为了探索 IA 的生物学异质性，我们使用聚类方法将样品分为具有相似基因表达模式的亚组。
聚类分析将颞浅动脉和未破裂的 IA 聚集到它们自己的簇中，而 RIA 则分为 2 个不同的亚组（早期和晚期 RIA）。比较早期 RIA 和未破裂的 IA 之间的基因表达水平，我们在早期 RIA 中鉴定出 430 个上调和 617 个下调基因。上调的基因与炎症和免疫反应以及吞噬作用有关，包括 S100/钙粒蛋白基因（S100A8、S100A9 和 S100A12）。下调的基因表明动脉瘤壁的机械强度较弱。转录因子的 Krüppel 样家族（KLF2、KLF12 和 KLF15）和 CDKN2A 的表达也下调，CDKN2A 位于染色体 9p21 上，该基因在 IA 的全基因组关联研究中是最一致的复制基因座，CDKN2A 是一个抗炎调节因子。
我们证明 RIA 的基因表达模式根据患者的年龄而不同。结果表明，巨噬细胞介导的炎症是 IA 破裂的关键生物学途径。鉴定出的基因可以作为易破裂 IA 的分子标志物和治疗靶点的良好候选物。
