Peng Qian, Dai Zhun, Yin Jingwen, Lv Dong, Luo Xudong, Xiong Susu, Yang Zhijiang, Chen Guangmin, Wei Yaxue, Wang Ying, Zhang Dandan, Wang Lulu, Yu Debo, Zhao Yusheng, Lin Dele, Liao Zhiyu, Zhong Yongxi, Lin Zhixiong, Lin Juda
Department of Psychiatry, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Front Psychiatry. 2023 Aug 23;14:1187111. doi: 10.3389/fpsyt.2023.1187111. eCollection 2023.
Schizophrenia (SCZ) is a serious chronic mental disorder. Our previous case-control genetic association study has shown that microRNA-137 (miR-137) may only protect females against SCZ. Since estrogen, an important female sex hormone, exerts neuroprotective effects, the relationship between estrogen and miR-137 in the pathophysiology of SCZ was further studied in this study.
Genotyping of single-nucleotide polymorphism rs1625579 of miR-137 gene in 1,004 SCZ patients and 896 healthy controls was conducted using the iMLDR assay. The effect of estradiol (E2) on the miR-137 expression was evaluated on the human mammary adenocarcinoma cell line (MCF-7) and the mouse hippocampal neuron cell line (HT22). The relationships between serum E2, prolactin (PRL), and peripheral blood miR-137 were investigated in 41 SCZ patients and 43 healthy controls. The miR-137 and other reference miRNAs were detected by real-time fluorescent quantitative reverse transcription-PCR.
Based on the well-known SNP rs1625579, the distributions of protective genotypes and alleles of the miR-137 gene were not different between patients and healthy controls but were marginally significantly lower in female patients. E2 upregulated the expression of miR-137 to 2.83 and 1.81 times in MCF-7 and HT22 cells, respectively. Both serum E2 and blood miR-137 were significantly decreased or downregulated in SCZ patients, but they lacked expected positive correlations with each other in both patients and controls. When stratified by sex, blood miR-137 was negatively correlated with serum E2 in female patients. On the other hand, serum PRL was significantly increased in SCZ patients, and the female patients had the highest serum PRL level and a negative correlation between serum PRL and blood miR-137.
The plausible SCZ-protective effect of miR-137 may be female specific, of which the underlying mechanism may be that E2 upregulates the expression of miR-137. This protective mechanism may also be abrogated by elevated PRL in female patients. These preliminary findings suggest a new genetic/environmental interaction mechanism for E2/miR-137 to protect normal females against SCZ and a novel E2/PRL/miR-137-related pathophysiology of female SCZ, implying some new antipsychotic ways for female patients in future.
精神分裂症（SCZ）是一种严重的慢性精神障碍。我们之前的病例对照基因关联研究表明，微小RNA-137（miR-137）可能仅对女性起到预防SCZ的作用。由于雌激素作为一种重要的女性性激素具有神经保护作用，本研究进一步探讨了雌激素与miR-137在SCZ病理生理学中的关系。
采用iMLDR分析法对1004例SCZ患者和896例健康对照者的miR-137基因单核苷酸多态性rs1625579进行基因分型。在人乳腺腺癌细胞系（MCF-7）和小鼠海马神经元细胞系（HT22）上评估雌二醇（E2）对miR-137表达的影响。在41例SCZ患者和43例健康对照者中研究血清E2、催乳素（PRL）与外周血miR-137之间的关系。通过实时荧光定量逆转录PCR检测miR-137和其他参考微小RNA。
基于已知的单核苷酸多态性rs1625579，miR-137基因的保护性基因型和等位基因在患者和健康对照者之间的分布没有差异，但在女性患者中略低。E2分别将MCF-7和HT22细胞中miR-137的表达上调至2.83倍和1.81倍。SCZ患者的血清E2和血液miR-137均显著降低或下调，但在患者和对照者中它们之间均缺乏预期的正相关。按性别分层时，女性患者的血液miR-137与血清E2呈负相关。另一方面，SCZ患者的血清PRL显著升高，女性患者的血清PRL水平最高，且血清PRL与血液miR-137呈负相关。
miR-137可能对SCZ具有的保护作用可能具有女性特异性，其潜在机制可能是E2上调miR-137的表达。女性患者中升高的PRL可能也会破坏这种保护机制。这些初步研究结果提示了一种新的E2/miR-137基因/环境相互作用机制，该机制可保护正常女性免受SCZ侵害，以及一种新的与女性SCZ相关的E2/PRL/miR-137病理生理学机制，这意味着未来可能为女性患者提供一些新的抗精神病治疗方法。
