Genetic association study identifies a functional CNV in the WWOX gene contributes to the risk of intracranial aneurysms.

Jin Fan,Dan Duan,Jian Wang,Min Lin,Qingsong Wang,Ke Yu,Bo Zheng,Wen Sun,Zhenghui Yang

doi:10.18632/oncotarget.7546

Abstract

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.

Highlights

Intracranial aneurysms (IAs) account for about 80–85% of non-traumatic subarachnoid hemorrhages (SAH) [1,2,3]
When analyzing the data using a log-additive model and adjusted for age, gender, smoking status, and Hypertension, we found that there was a significantly higher risk of IAs for per copy deletion (OR = 1.43, 95% confidence intervals (CIs) = 1.14–1.80; Ptrend = 1.79 × 10−3)
Exploration of copy number variations (CNVs) and their role in carcinogenesis could possess a large number of potential clues for developing novel therapeutic agents for IAs

Summary

Introduction

Intracranial aneurysms (IAs) account for about 80–85% of non-traumatic subarachnoid hemorrhages (SAH) [1,2,3]. The prevalence of IAs is about 1–5% (10 million to 12 million persons in the United States) and the incidence is 1 per 10,000 persons per year in the United States (approximately 27,000), with incidence highest in 30- to 60-year-olds [4, 5]. Women own more cases of IAs, by a ratio of 3 to 2 [4]. Previous studies have indicated that hypertension, hypercholesterolemia, cigarette smoking and female gender are risk factors for IAs [7]. There is increasing evidence to suggest that genetic factors play an important part in the pathogenesis of IAs [6, 8, 9]

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Conclusion