颅内动脉瘤与基因变异、转录异常及基因甲基化变化的关联。
Intracranial aneurysm's association with genetic variants, transcription abnormality, and methylation changes in genes.
作者信息
Chen Shi, Li Mengqi, Xin Wenqiang, Liu Shengze, Zheng Linfei, Li Yan, Li Mengyao, Zhan Mengxiong, Yang Xinyu
机构信息
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
Department of Neurosurgery, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, Fujian, China.
出版信息
PeerJ. 2020 Feb 14;8:e8596. doi: 10.7717/peerj.8596. eCollection 2020.
PURPOSE
The development of intracranial aneurysm (IA) has been linked to genetic factors. The current study examines the potential role of genes encoding disintegrin and metalloproteinase using thrombospondin motifs (ADAMTS) in IA development.
MATERIAL AND METHODS
High-throughput whole-genome and whole-exome sequencing were used when screening for deleterious single-nucleotide variants (SNVs) in genes using samples from 20 Han Chinese patients: 19 with familial IA and one patient with sporadic IA. The variant frequencies in these subjects were compared to those in control individuals found in the Genome Aggregation Database. Transcriptome sequencing and methylation sequencing data were retrieved from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes and their methylation sites. We predicted the network of interactions among proteins encoded by the overlapping set of genes showing deleterious variants and both differential expression and abnormal methylation in IA. Possible candidate proteins linked to IA were validated using Western blot analysis. The associations between IA and SNVs rs11750568 in , as well as rs2301612 and rs2285489 in , were verified using the Sequenom MassArray system on a separate sample set of 595 Han Chinese patients with sporadic IA and 600 control individuals.
RESULTS
A total of 16 deleterious variants in 13 genes were identified in our patients, and seven of these genes overlapped with the genes found to be differentially expressed and differentially methylated in the GEO database. Protein-protein interaction analysis predicted that ADAMTSL1 was at the center of the seven genes. ADAMTSL1 protein was lower expressed in IA tissue than in the control cerebral artery. Frequencies of the IA-related SNVs rs11750568 in ADAMTS2 and rs2301612 and rs2285489 in were not significantly different between sporadic IA patients and controls.
CONCLUSION
IA is associated with genetic variants, differential expression, and abnormal methylation in genes, in particular.
目的
颅内动脉瘤（IA）的发生与遗传因素有关。本研究探讨了含血小板反应蛋白基序的解整合素和金属蛋白酶（ADAMTS）编码基因在IA发生中的潜在作用。
材料与方法
使用来自20例汉族患者的样本进行高通量全基因组和全外显子组测序，以筛选基因中的有害单核苷酸变异（SNV）：19例家族性IA患者和1例散发性IA患者。将这些受试者的变异频率与基因组聚合数据库中对照个体的变异频率进行比较。从基因表达综合数据库（GEO）中检索转录组测序和甲基化测序数据，以鉴定差异表达基因及其甲基化位点。我们预测了在IA中显示有害变异以及差异表达和异常甲基化的重叠基因集所编码蛋白质之间的相互作用网络。使用蛋白质印迹分析验证与IA相关的可能候选蛋白。在595例汉族散发性IA患者和600例对照个体的单独样本集上，使用Sequenom MassArray系统验证了IA与ADAMTS2中SNV rs11750568以及ADAMTS1中rs2301612和rs2285489之间的关联。
结果
在我们的患者中，共鉴定出13个基因中的16个有害变异，其中7个基因与在GEO数据库中发现的差异表达和差异甲基化的基因重叠。蛋白质-蛋白质相互作用分析预测ADAMTSL1位于这7个基因的中心。ADAMTSL1蛋白在IA组织中的表达低于对照脑动脉。散发性IA患者和对照之间，ADAMTS2中与IA相关的SNV rs11750568以及ADAMTS1中rs2301612和rs2285489的频率无显著差异。
结论
IA与基因中的遗传变异、差异表达和异常甲基化有关，尤其是ADAMTS基因。
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