Genetic association study identifies a functional CNV in the WWOX gene contributes to the risk of intracranial aneurysms
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Jin Fan1, Wen Sun2, Min Lin3, Ke Yu1, Jian Wang1, Dan Duan1, Bo Zheng1, Zhenghui Yang1, Qingsong Wang1
1Department of Neurology, Chengdu Military General Hospital, Chengdu, China
2Department of Neurology, Jinling Hospital of Nanjing University, Nanjing, China
3Department of Neurology, Fuzhou General Hospital of Nanjing Command, PLA and Clinical Medical College of Fujian Medical University, Fuzhou, China
Qingsong Wang, e-mail: firstname.lastname@example.org
Keywords: intracranial aneurysm, gene, SNP, risk factor, WWOX
Received: October 09, 2015 Accepted: January 31, 2016 Published: February 21, 2016
Intracranial aneurysms (IAs) accounts for 85% of hemorrhagic stroke. Genetic factors have been known to play an important role in the development of IAs. A functional CNV (CNV-67048) of human WW domain-containing oxidoreductase (WWOX), which has been identified as a tumor suppressor gene in multiple cancers, was identified to be associated with gliomas risk previously. Here, we hypothesized that the CNV-67048 could also affect susceptibility of IAs. Based on a two-stage, case− control study with a total of 976 patients of IAs and 1,200 matched healthy controls, we found the effect size for per copy deletion was 1.35 (95% CI = 1.16–1.57; Ptrend = 1.18 × 10−4). Compared with the individuals having no deletion, significantly higher risk of IAs was detected for both subjects carrying 1 copy deletion (OR = 1.24, 95% CI = 1.02–1.52) and subjects carrying 2 copy deletion (OR = 1.77, 95% CI = 1.24–2.53). Real-time PCR was used to confirm the abnormal expression of WWOX in tissues of IA patients and influence of genotypes of CNV-67048. The expression level of WWOX in IA tissues was significantly lower than that in corresponding normal tissues (P = 0.004), and the deletion genotypes of CNV-67048 have lower WWOX mRNA levels in both tumor tissues and border tissues (P < 0.01). Our data suggests that the deletion genotypes of CNV-67048 in WWOX predispose their carriers to IAs, which might be a genetic biomarker to predict risk of IAs in Chinese.
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