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.
Keywords: Brain arteriovenous malformations; Cyclin-dependent kinase inhibitor 2A; DNA methylation; Epigenetics; Intracranial aneurysms.