Chen Linfa, Wei Shan, Zhang Yutian, Li You, Li Zishan, Huang Pengru, Xiao Chun, Zhang Yusheng
Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China.
Huizhou Third People's Hospital, Guangzhou Medical University, Huizhou, 516002, People's Republic of China.
Int J Gen Med. 2025 May 22;18:2659-2672. doi: 10.2147/IJGM.S524033. eCollection 2025.
Single nucleotide polymorphisms (SNPs) at microRNA (miRNA)--binding sites influence the development of ischemic stroke (IS) by affecting the expression of specific target genes. Myotubularin-related protein 3 (MTMR3), which is involved in autophagy, is directly targeted by miR-181a. This research examined the potential association between the SNP rs12537 in the miRNA-181a binding location within the 3' untranslated region (3'-UTR) of MTMR3 and the incidence and prognosis of IS.
An improved multitemperature ligase detection reaction assay was used to perform genotyping analysis in two independent case-control datasets consisting of 1128 subjects with IS and 1140 healthy controls with matched ages.
The distribution frequencies of the T allele ( = 5.2×10) of SNP rs12537 in MTMR3 were elevated significantly in IS patients as compared to healthy controls. Further categorization based on IS subtypes revealed that individuals carrying the variation T allele were linked with a higher risk of suffering large-artery ( = 1.2×10) and small-artery ( = 7.0×10) atherosclerotic stroke subtypes. The T allele of rs12537 was shown to be linked to both moderate and severe stroke (NIHSS ≥ 6) ( = 0.011), as well as a poor short-term outcome ( = 0.016) of IS. A significant correlation was also found between the rs12537 T allele mutation and a decrease in MTMR3 ( = 0.019), as well as an elevated miR-181a ( = 0.021) and LC3B ( = 0.026) in individuals with IS.
This study identified a novel role for the rs12537 variant in influencing IS susceptibility and prognosis, potentially by modulating MTMR3 expression and leading to increased autophagy.
微小RNA（miRNA）结合位点的单核苷酸多态性（SNP）通过影响特定靶基因的表达来影响缺血性中风（IS）的发生发展。参与自噬的肌管素相关蛋白3（MTMR3）是miR-181a的直接靶标。本研究探讨了MTMR3 3'非翻译区（3'-UTR）中miRNA-181a结合位点的SNP rs12537与IS的发病率和预后之间的潜在关联。
采用改进的多温度连接酶检测反应分析法，对两个独立的病例对照数据集进行基因分型分析，其中包括1128例IS患者和1140例年龄匹配的健康对照。
与健康对照相比，IS患者中MTMR3基因SNP rs12537的T等位基因（=5.2×10）分布频率显著升高。根据IS亚型进一步分类显示，携带变异T等位基因的个体患大动脉（=1.2×10）和小动脉（=7.0×10）动脉粥样硬化性中风亚型的风险更高。rs12537的T等位基因与中度和重度中风（美国国立卫生研究院卒中量表≥6）（=0.011）以及IS的短期预后不良（=0.016）相关。在IS患者中，还发现rs12537 T等位基因突变与MTMR3降低（=0.019）、miR-181a升高（=0.021）和LC3B升高（=0.026）之间存在显著相关性。
本研究确定了rs12537变异在影响IS易感性和预后方面的新作用，可能是通过调节MTMR3表达并导致自噬增加来实现的。
