DNA Methylation of Patatin-Like Phospholipase Domain-Containing Protein 6 Gene Contributes to the Risk of Intracranial Aneurysm in Males

Shengjun Zhou; Junjun Zhang; Chenhui Zhou; Fanyong Gong; Xueli Zhu; Xingqiang Pan; Jie Sun; Xiang Gao; Yi Huang

doi:10.3389/fnagi.2022.885680

DNA Methylation of Patatin-Like Phospholipase Domain-Containing Protein 6 Gene Contributes to the Risk of Intracranial Aneurysm in Males

Front Aging Neurosci. 2022 Jul 11:14:885680. doi: 10.3389/fnagi.2022.885680. eCollection 2022.

Authors

Shengjun Zhou^{1

2}, Junjun Zhang¹, Chenhui Zhou^{1

2}, Fanyong Gong¹, Xueli Zhu³, Xingqiang Pan⁴, Jie Sun¹, Xiang Gao¹, Yi Huang^{1

2

5}

Affiliations

¹ Department of Neurosurgery, Ningbo First Hospital, Ningbo, China.
² Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, China.
³ Department of Ultrasound, Ningbo First Hospital, Ningbo, China.
⁴ Ningbo Center for Disease Control and Prevention, Ningbo, China.
⁵ Medical Research Center, Ningbo First Hospital, Ningbo, China.

Abstract

Objective: This study is aimed to investigate the contribution of patatin-like phospholipase domain-containing protein 6 (PNPLA6) DNA methylation to the risk of intracranial aneurysm (IA) in the Han Chinese population. Methods: A total of 96 age- and sex-matched participants were recruited to evaluate PNPLA6 methylation via bisulfite pyrosequencing. The PNPLA6 mRNA expression in the plasma was determined using real-time quantitative reverse transcription-polymerase chain reaction. Human primary artery smooth muscle cells (HPCASMC) were used for the in vitro function study. Results: PNPLA6 methylation was significantly higher in patients with IA than in healthy controls (p < 0.01). Sex group analysis showed that this correlation appeared in the male group (p < 0.01) but not in the female group (p > 0.05). PNPLA6 methylation was significantly associated with age in all participants (r = 0.306, p = 0.003) and in the control group (r = 0.377, p = 0.008) but not in the IA group (r = 0.127, p = 0.402). Furthermore, the PNPLA6 mRNA expression significantly decreased in patients with IA than that in the controls (p = 0.016). PNPLA6 expression was significantly inversely correlated with elevated DNA methylation in participants (r = -0.825, p < 0.0001). In addition, PNPLA6 transcription was significantly enhanced following treatment with 5-aza-2'-deoxycytidine methylation inhibitor in HPCASMC.The receiver operating characteristic analyses of curves showed that the PNPLA6 mean methylation [area under the curve (AUC) = 0.74, p < 0.001] and mRNA expression (AUC = 0.86, p < 0.001) could have a diagnostic value for patients with IA. Conclusion: Although future functional experiments are required to test our hypothesis, our study demonstrated that PNPLA6 methylation and mRNA expression were significantly associated with the risk of IA; thus, they show potential for use in the early diagnosis of IA.

Keywords: DNA methylation; PNPLA6; age; intracranial aneurysms; mRNA expression.