Sex-Specific X-Chromosome Gene Expression in Intracranial Aneurysms

BackgroundWomen have a higher prevalence of intracranial aneurysms (IAs) than men, but the biological basis for this difference is unclear. Some X-chromosome genes escape inactivation and may contribute to sex-specific susceptibility. This study aimed to identify gene expression differences associated with unruptured IA and to determine whether X-linked gene expressions differ by sex. MethodsWhole-blood RNA sequencing was performed in 166 individuals, including 129 patients with unruptured IAs (108 women and 21 men) and 37 controls (14 women and 23 men). Differential gene expression was evaluated using edgeR with a false discovery rate threshold q-value=0.05. Sex-stratified analyses were conducted to study X-linked expression patterns in women and men separately. CDK16, the leading X-linked candidate, was validated by real-time quantitative PCR (RT-qPCR) in an independent cohort of 55 individuals with 32 IA cases (20 women and 12 men) and 23 controls (11 women and 12 men). ResultsSeven genes were differentially expressed in IA versus controls (HBG2, AP3B2, COL7A1, CDK16, NUP210L, KDM5C, HSPA1L), including two X-linked genes: CDK16 (log2FC 0.23, q-value=0.018), and KDM5C (log2FC 0.32, q-value=0.04). CDK16 showed a strong sex-specific pattern where the expression was higher in women with IA compared to female controls, and no difference was observed between male IA and controls. RT-qPCR confirmed the sex-dependent differential expression of CDK16 (p<0.01). ConclusionsUnruptured IA is associated with distinct blood transcriptional changes, including differential expression of X-linked genes. Additionally, CDK16 emerges as a potential female-specific biomarker, suggesting a mechanism involving escape from X-inactivation. These findings support further investigation of X-chromosomal regulation in the female predominance of IA and may inform future diagnostic and therapeutic strategies.