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Methylation of the CDKN2A Gene Increases the Risk of Brain Arteriovenous Malformations

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Abstract

Brain arteriovenous malformations (BAVMs) and intracranial aneurysms (IAs) are the results of a combination of genetic and environmental factors. Epigenetic factors also play an important role in the pathogenesis of these disorders. The aim of this study was to determine the effect of DNA methylation at the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene on the risk of BAVMs and IAs. A total of 70 intracranial vascular malformation patients (22 patients with BAVMs and 48 patients with IAs) and 26 patients with cerebral trauma (used as controls) were included in this study. DNA methylation levels of eight cytosine-phosphate-guanine (CpG) dinucleotides present in the CDKN2A gene were measured using bisulfite pyrosequencing technology. Significant differences in methylation at CpG1 (p = 0.005), CpG5 (p = 0.011), and CpG8 (p = 0.017) were observed between BAVM patients and controls. CDKN2A methylation levels in BAVM patients were much higher than those in IA patients (CpG5: p = 0.004; CpG8: p = 0.010). Significant differences were observed between female IA patients and female BAVM patients (CpG5: p = 0.006; CpG8: p = 0.005; mean: p = 0.015). Receiver operating characteristic (ROC) curve analysis showed that the CDKN2A gene methylation trended toward a diagnostic indicator in BAVM patients (area under curve = 0.711, p = 0.013). In conclusion, our study demonstrated that the CDKN2A gene methylation levels are significantly correlated with the occurrence of BAVMs, and thus, have potential for use in the early diagnosis of BAVMs. Future research on the pathogenesis of BAVMs should focus on the role of genetic factors in aberrant venous development. The association of the CDKN2A gene with venous development also deserves further study.

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Abbreviations

IAs:

Intracranial aneurysms

BAVMs:

Brain arteriovenous malformations

CDKN2A:

Cyclin-dependent kinase inhibitor 2A

CpGs:

Cytosine-phosphate guanine sequences

GWAS:

Genome-wide association studies.

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Funding

This study was supported by the grants from the Zhejiang Provincial Natural Science Foundation of China (LQ17H090002, LQ18H090002), the Medicine and health science and technology projects of Zhejiang province (2018KY665, 2017KY610), the Ningbo Natural Science Foundation (2017A610223), and the Ningbo Health Branding Subject Fund (PPXK2018-04).

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Authors and Affiliations

  1. Department of Neurosurgery, Ningbo First Hospital, Ningbo University School of Medicine, No.59 Liuting Street, Ningbo, 315010, Zhejiang, China

    Xiaosheng Chen, Yuchun Liu, Shengjun Zhou, Sheng Nie, Zhiqin Lin, Chenhui Zhou, Jie Sun, Xiang Gao & Yi Huang

  2. Department of Neurosurgery, Ningbo Hospital, Zhejiang University School of Medicine, Ningbo, 315010, Zhejiang, China

    Yuchun Liu, Shengjun Zhou, Sheng Nie, Zhiqin Lin, Chenhui Zhou, Jie Sun, Xiang Gao & Yi Huang

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  1. Xiaosheng Chen
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  2. Yuchun Liu
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  3. Shengjun Zhou
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  4. Sheng Nie
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  7. Jie Sun
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  9. Yi Huang
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Contributions

JS, XG, and YH designed the study and edited the manuscript. XC, YL, ZL, SN, CZ, and SZ were responsible for data acquisition and experiments. XC and YL conducted data analysis and drafted the manuscript.

Corresponding authors

Correspondence to Jie Sun, Xiang Gao or Yi Huang.

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All experiments were approved by the Ethics Committee of Ningbo First Hospital and written informed consent was given by all participants.

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The authors declare that they have no conflict of interest.

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Chen, X., Liu, Y., Zhou, S. et al. Methylation of the CDKN2A Gene Increases the Risk of Brain Arteriovenous Malformations. J Mol Neurosci 69, 316–323 (2019). https://doi.org/10.1007/s12031-019-01360-6

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  • DOI: https://doi.org/10.1007/s12031-019-01360-6

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