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

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

Shengjun Zhou  1   2 , Junjun Zhang  1 , Chenhui Zhou  1   2 , Fanyong Gong  1 , Xueli Zhu  3 , Xingqiang Pan  4 , Jie Sun  1 , Xiang Gao  1 , Yi Huang  1   2   5
Affiliations

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

Shengjun Zhou et al. Front Aging Neurosci. .

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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The locations and analysis of the five CpGs in PNPLA6 gene. (A) The locations of the five CpGs in PNPLA6 gene. (B) Representative sequencing analysis of five methylation sites.
Figure 2
Figure 2
The correlations among GpGs methylation and clinical data in different subgroups. (A) The correlation analysis in all groups. (B) The correlation analysis in the control group. (C) The correlation analysis in IA group. The correlations among the five CpGs methylation were analyzed using Pearson’s correlation test, **p < 0.01; *p < 0.05.
Figure 3
Figure 3
Comparison of the five GpGs methylation levels in different subgroups. (A) The comparison between controls and IAs in males and females. (B) The comparison between controls and IAs in males. (C) The comparison between controls and IAs in females. (D) The comparison between males and females in the control group. (E) The comparison between males and females in the IA group. (F) The comparison between ruptured IA and unruptured IA. Data were represented as mean ± SD.
Figure 4
Figure 4
The relationship between PNPLA6 methylations and age in different subgroups. (A) The relationship analysis in all participants. (B) The relationship analysis in the control group. (C) The relationship analysis in the IA group.
Figure 5
Figure 5
The significant association between PNPLA6 mRNA expression and DNA methylation. (A) PNPLA6 mRNA expression was much lower in IAs than in healthy controls. (B) The PNPLA6 expression was significantly associated with DNA methylation in all individuals. (C) The changes of PNPLA6 expression in the cell lines treated with AZA.
Figure 6
Figure 6
ROC curves of PNPLA6 DNA methylation in IA patients. ROC, receiver operating characteristic. AUC, area under the curve.
See this image and copyright information in PMC

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