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Circ Genom Precis Med. 2018 Jul;11(7):e002099. doi: 10.1161/CIRCGEN.117.002099.

Rho Guanine Nucleotide Exchange Factor ARHGEF17 Is a Risk Gene for Intracranial Aneurysms.

Author information

1
Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China (X.Y., Z.Z., Y.Z., M.L., L.H., R.J., S.Y., J.Z., F.Y.).
2
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX (J.L., F.Y.).
3
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhong Shan Hospital, Fudan University, Shanghai, China (Y.F., D.J., X.C., L.J., T.P.Z.).
4
Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences (Y.F., D.J., L.J., T.P.Z.).
5
Department of Neurosurgery, Linyi People's Hospital, Shandong, China (L.H.).
6
Engineering Medicine, Texas A&M Health Science Center and College of Engineering, Houston (T.A.K.).
7
Blood Works Northwest Research Institute, Seattle, WA (J.-F.D.).
8
Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle (J.-F.D.).
9
Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China (X.Y., Z.Z., Y.Z., M.L., L.H., R.J., S.Y., J.Z., F.Y.). fyu@bcm.edu taozhong@fudan.edu.cn jianningzhang@hotmail.com.
10
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhong Shan Hospital, Fudan University, Shanghai, China (Y.F., D.J., X.C., L.J., T.P.Z.). fyu@bcm.edu taozhong@fudan.edu.cn jianningzhang@hotmail.com.

Abstract

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.

KEYWORDS:

genomics; hemorrhage; human genetics; intracranial aneurysm; subarachnoid; zebrafish

PMID:
29997225
PMCID:
PMC6141028
[Available on 2019-07-01]
DOI:
10.1161/CIRCGEN.117.002099

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