Sex-dichotomous effects of NOS1AP promoter DNA methylation on intracranial aneurysm and brain arteriovenous malformation

The goal of this study was to investigate the contribution of NOS1AP-promoter DNA methylation to the risk of intracranial aneurysm (IA) and brain arteriovenous malformation (BAVM) in a Han Chinese population. A total of 48 patients with IAs, 22 patients with BAVMs, and 26 control individuals were enrolled in the study. DNA methylation was tested using bisulfite pyrosequencing technology. We detected significantly higher DNA methylation levels in BAVM patients than in IA patients based on the multiple testing correction (CpG4-5 methylation: 5.86 ± 1.04% vs. 4.37 ± 2.64%, P = 0.006). In women, CpG4-5 methylation levels were much lower in IA patients (3.64 ± 1.97%) than in BAVM patients (6.11 ± 1.20%, P < 0.0001). However, in men, CpG1-3 methylation levels were much higher in the controls (6.92 ± 0.78%) than in BAVM patients (5.99 ± 0.70%, P = 0.008). Additionally, there was a gender-based difference in CpG1 methylation within the controls (men vs. women: 5.75 ± 0.50% vs. 4.99 ± 0.53%, P = 0.003) and BAVM patients (men vs. women: 4.70 ± 0.74% vs. 5.50 ± 0.87%, P = 0.026). A subgroup analysis revealed significantly higher CpG3 methylation in patients who smoked than in those who did not (P = 0.041). Our results suggested that gender modulated the interaction between NOS1AP promoter DNA methylation in IA and BAVM patients. Our results also confirmed that regular tobacco smoking was associated with increased NOS1AP methylation in humans. Additional studies with larger sample sizes are required to replicate and extend these findings.