RNA Sequencing Analysis of Intracranial Aneurysm Walls Reveals Involvement of Lysosomes and Immunoglobulins in Rupture
RNA Sequencing Analysis of Intracranial Aneurysm Walls Reveals Involvement of Lysosomes and Immunoglobulins in Rupture
复制标题
DOI：
10.1161/strokeaha.116.012541
复制
发表时间：
2016-05-01
期刊：
影响因子：
8.3
通讯作者：
Ruigrok, Ynte M.
中科院分区：
文献类型：
--
作者：
Kleinloog, Rachel;Verweij, Bon H.;Ruigrok, Ynte M.
背景和目的-分析与颅内动脉瘤发生和破裂有关的基因有助于提高对动脉瘤发病机制的认识，并确定新的治疗策略。我们比较了破裂和未破裂的动脉瘤和对照颅内动脉的基因表达。方法：我们用RNA测序法测定基因表达水平。应用多变量负二项模型，我们确定了44个动脉瘤和16个对照动脉以及22个破裂和21个未破裂动脉瘤之间差异表达的基因。用数字聚合酶链式反应验证8个相关和高度显著基因的差异表达。途径分析被用来确定丰富的途径。我们还分析了具有极端差异表达模式的基因：只在一种情况下表达，而在另一种情况下没有表达。结果-我们发现229个差异表达基因在动脉瘤与对照组之间，1489个在破裂与未破裂的动脉瘤中。为数字化聚合酶链式反应验证选择的所有8个基因的差异表达得到证实。与对照组相比，细胞外基质途径在动脉瘤中丰富，而参与免疫反应的途径和溶酶体途径在破裂与未破裂的动脉瘤中丰富。免疫球蛋白基因在动脉瘤中表达，而在对照组中未见表达。结论--在颅内动脉瘤破裂过程中，我们发现溶酶体途径是一种新的途径，并为免疫反应的作用提供了进一步的证据。我们的结果也指出免疫球蛋白在动脉瘤的发病机制中的作用。因此，免疫调节药物在预防动脉瘤的发展和破裂方面是有趣的候选治疗策略。
Background and Purpose-Analyzing genes involved in development and rupture of intracranial aneurysms can enhance knowledge about the pathogenesis of aneurysms, and identify new treatment strategies. We compared gene expression between ruptured and unruptured aneurysms and control intracranial arteries.Methods-We determined expression levels with RNA sequencing. Applying a multivariate negative binomial model, we identified genes that were differentially expressed between 44 aneurysms and 16 control arteries, and between 22 ruptured and 21 unruptured aneurysms. The differential expression of 8 relevant and highly significant genes was validated using digital polymerase chain reaction. Pathway analysis was used to identify enriched pathways. We also analyzed genes with an extreme pattern of differential expression: only expressed in 1 condition without any expression in the other.Results-We found 229 differentially expressed genes in aneurysms versus controls and 1489 in ruptured versus unruptured aneurysms. The differential expression of all 8 genes selected for digital polymerase chain reaction validation was confirmed. Extracellular matrix pathways were enriched in aneurysms versus controls, whereas pathways involved in immune response and the lysosome pathway were enriched in ruptured versus unruptured aneurysms. Immunoglobulin genes were expressed in aneurysms, but showed no expression in controls.Conclusions-For rupture of intracranial aneurysms, we identified the lysosome pathway as a new pathway and found further evidence for the role of the immune response. Our results also point toward a role for immunoglobulins in the pathogenesis of aneurysms. Immune-modifying drugs are, therefore, interesting candidate treatment strategies in the prevention of aneurysm development and rupture.