Rho Guanine Nucleotide Exchange Factor ARHGEF17 Is a Risk Gene for Intracranial Aneurysms.
Rho Guanine Nucleotide Exchange Factor ARHGEF17 Is a Risk Gene for Intracranial Aneurysms.
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Rho鸟嘌呤核苷酸交换因子ARHGEF17是颅内动脉瘤的危险基因
DOI：
10.1161/circgen.117.002099
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发表时间：
2018-07
期刊：
影响因子：
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通讯作者：
Yu F
中科院分区：
文献类型：
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作者：
Yang X;Li J;Fang Y;Zhang Z;Jin D;Chen X;Zhao Y;Li M;Huan L;Kent TA;Dong JF;Jiang R;Yang S;Jin L;Zhang J;Zhong TP;Yu F
背景资料：颅内动脉瘤（IA）通常是一种迟发性疾病，影响1%至3%的普通人群，并导致危及生命的蛛网膜下腔出血。遗传易感性与IA有关，但致病基因仍然难以捉摸。方法：我们对20名中国IA患者的发现队列进行了下一代测序。利用生物信息学过滤器来搜索具有罕见和低等位基因频率的候选有害变体。我们进一步研究了来自3个先前发表的研究的86个全外显子测序的未解决的家族性IA病例的多种族样本集合中的候选变体。结果如下：我们发现，ARHGEF 17的低频变异c.4394C>A_p.Ala1465Asp（rs 2298808）与我们中国发现队列中的IA显著相关（P=7.3×10−4;比值比=7.34）。随后在日本家族性IA患者中重复（P=0.039;比值比=4.00; 95%置信区间=0.832-14.8），并在包括832例散发性IA受影响者和599例对照个体的大型中国样本收集中与IA相关（P=0.041;比值比=1.51; 95%置信区间=1.02-Inf）。当结合来自4个不同种族（即中国人、日本人、欧洲裔美国人和法裔加拿大人）的所有家族性IA患者的测序数据时，我们发现与对照组相比，病例中ARHGEF 17的突变负荷显著增加（21/106 vs. 11/306; P=8.1×10−7;比值比=6.6; 95%置信区间=2.9-15.8）。在斑马鱼中，arhgef 17在脑血管中高度表达。arhgef 17敲低引起脑区的血液外渗。在arhgef 17缺陷斑马鱼的脑血管中专门发现了内皮损伤。结论：我们的研究结果提供了令人信服的证据，ARHGEF 17是IA的风险基因。
Background: Intracranial aneurysm (IA) is usually a late-onset disease, affecting 1% to 3% of the general population and leading to life-threatening subarachnoid hemorrhage. Genetic susceptibility has been implicated in IAs, but the causative genes remain elusive. Methods: We performed next-generation sequencing in a discovery cohort of 20 Chinese IA patients. Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency. We further examined the candidate variants in a multiethnic sample collection of 86 whole exome sequenced unsolved familial IA cases from 3 previously published studies. Results: We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp (rs2298808) of ARHGEF17 was significantly associated with IA in our Chinese discovery cohort (P=7.3×10−4; odds ratio=7.34). It was subsequently replicated in Japanese familial IA patients (P=0.039; odds ratio=4.00; 95% confidence interval=0.832–14.8) and was associated with IA in the large Chinese sample collection comprising 832 sporadic IA-affected and 599 control individuals (P=0.041; odds ratio=1.51; 95% confidence interval=1.02-Inf). When combining the sequencing data of all familial IA patients from 4 different ethnicities (ie, Chinese, Japanese, European American, and French-Canadian), we identified a significantly increased mutation burden for ARHGEF17 (21/106 versus 11/306; P=8.1×10−7; odds ratio=6.6; 95% confidence interval=2.9–15.8) in cases as compared with controls. In zebrafish, arhgef17 was highly expressed in the brain blood vessel. arhgef17 knockdown caused blood extravasation in the brain region. Endothelial lesions were identified exclusively on cerebral blood vessels in the arhgef17-deficient zebrafish. Conclusions: Our results provide compelling evidence that ARHGEF17 is a risk gene for IA.