Numerous predisposing risk factors involved in LAA stroke. Genetic factors can explain the risk of stroke which cannot be covered by traditional risk factors. Heritability for LAA stroke was described as 40.3% (Bevan et al. 2012). The genetic risk factors play significant roles in the diagnosis and prevention of LAA stroke. MiRNAs are a group of ncRNA with about 23 nucleotide length. They can regulate gene expression by targeting the 3’UTR of the mRNA. Growing evidence has indicated circulating miRNAs can be unique biomarkers for stroke diagnosis, prognosis, and therapy (Mirzaei et al. 2018). In previous studies, our team found that microRNA related SNPs can affect LAA stroke susceptibility (Wang et al. 2021).
The associations of SNPs in 5kb 5' flanking region of hsa-mir-451 with the LAA stroke risk were explored in our study. Our findings suggested that rs901975 (G > A) near hsa-mir-451 was associated with a decreased LAA stroke risk in Chinese population. The results of stratified analysis based on age, sex, hypertension, and diabetes for codominant and recessive genetic model of rs901975 were also significant. The protective effect of rs901975 A allele was also confirmed in other ethnic groups in MEGASTROKE.
In a research for human myocardial infarction (MI), miR-451 levels were up-regulated in 7-day MI (Bostjancic et al. 2009). The miR-451 is a special miRNA because pri-miR-451 is too short to be recognized by Dicer and it requires Argonaute2 catalytic activity (Cifuentes et al. 2010). Researchers often pay attention to miR-451 when they study miRNA function. miR-451 targets CUGBP Elav-like family member 2, which protects neurons from apoptosis and oxidative stress induced by oxygen and sugar deprivation/reoxygenation (Liu et al. 2018). By targeting TLR4, miR-451 could inhibit microglia activation-mediated inflammation, which is common in the injury and reparation of brain tissue in stroke (Sun and Zhang 2018). The miR-451 has protective effect on cerebral ischemia-reperfusion injury both in mice and human. It was speculated that higher miR-451 levels relate to a good prognosis for stroke patients. (Fu et al. 2019).
The rs9019751 is a common G > A variant on chromosome 17, 1kb 5' of miR-451. Unfortunately, there was no evidence that the miR-451 directly match rs901975 in the existing databases. SNP rs9019751 is in the intergenic region, between genes. Intergenic genomic sequences have been considered as desert DNA fragments in the past time. But it is currently known that approximately 98% of intergenic DNA sequences are related to ncRNA (Lander et al. 2001). Intergenic variants may cause disease through regulation of ncRNA expression. It has been found that some intergenic SNPs, such as rs12425791 within 11 kb of NINJ2 (Nie et al. 2019), can affect stroke susceptibility.
To date, no studies had shown the exact mechanism of the rs901975 regulating the function of miR-451 or other mRNAs. Parts of the associations between the rs901975 and clinical features have been researched. The rs901975 was found to associate with low-density lipoprotein (LDL) in a summary data-based Mendelian randomization (Pavlides et al. 2016). Thus, the rs901975 variant may participate in the process of lipid metabolism disorders in atherosclerosis. The vascular occlusion caused by atherosclerotic plaque and hemodynamic failure are main pathology induced LAA stroke. Oxidized low density lipoprotein (Ox-LDL) has been considered an important risk factor for vascular calcification and atherosclerosis. Knockdown of TLR4 reduced vascular calcification induced by Ox-LDL through nuclear factor kappa B (NK-κB) (Song et al. 2017). The rs901975 and miR-451 may be connected by TLR4. Therefore, we speculated that rs901975 is associated with high level of Ox-LDL, which can negatively regulate TLR4 level and thus increase the level of circulating miR-451. Although rs901975 cannot directly match miR-451 to regulate its circulating level, it can participate in miR-451 induced stroke through other molecular pathways.
In conclusion, our study indicated that the functional intergenic variants near miR-451 were significantly associated with LAA stroke risk. These findings need further functional studies and large population-based studies to verify.