In the current study, we explored the association between SNPs in the promoter of MALAT1 and risk of IS. Significant differences were observed in the distribution of the rs1194338 AC/AA genotype and A allele between controls and cases. Further analysis showed that MALAT1 rs1194338 A allele, AA, AC genotype and the dominant model were associated with decreased risk of IS. Regression analysis revealed that rs1194338AC/AA was one of impact factors of IS together with the lipid index such as TC, TG, HDL-C. In addition, haplotype analysis showed that the ACGC haplotype increased 1.3-fold risk of IS. These findings implicate that MALAT1 rs1194338 may played the role in the etiology of IS.
MALAT1, an 8.1 kb lncRNA, located on human chromosome 11q13. In 2003, Ji et al. first discovered and named MALAT1 from lung cancer cells . Subsequently, MALAT1 was confirmed to be associated with tumors cell proliferation, metastasis, survival, and recurrence . New evidence showed that MALAT1 was abundantly expressed in vascular endothelial cells and participated in processes of neuroprotection of IS by improvement of cognitive function, promotion of angiogenesis, inhibition of apoptosis and inflammation, regulation of autophagy, and protection of blood-brain barrier function [16-18, 28, 29]. The PI3K/AKT pathway was implicated in cell proliferation, apoptosis, and survival under physiological and pathological conditions . The previous study showed a neuroprotective role of early activation of PI3K in ischemic stroke . The result from Yuan et al. demonstrated that overexpression of MALAT1 decreased cell apoptosis by activating of PI3K/AKT pathway, eventually protect human cerebrovascular endothelial cells in OGD and reoxygenation condition . The above indicate that the MALAT1 plays a critical role in ischemic stroke, and its high expression may contribute to the protection against brain injury.
In recent years, the association between lncRNA related polymorphisms and risk of diseases has become hotpot of research. As a lncRNA with a wide range of functions, MALAT1 related SNPs attracted the attention of researchers. For instance, Eftekharian et al. explored the relationship between two MALAT1 SNPs (rs619586 and rs3200401) and multiple sclerosis (MS) in an Iranian population, and confirmed the G allele of rs619586 significantly reduced the risk of MS with OR of 0.65 . This means that functional SNPs of MALAT1 may serve as a potential indicator for relevant diseases. The ischemic stroke is one of the diseases threatening human health, and the pathogenesis of IS remain to be fully understood. Actually, increasing studies focused on SNPs of lncRNA involved in process of IS. For example, the rs2240183 C allele of lncRNA TUG1 was associated with a higher risk of IS by possibly binding to GATA‐1 and elevating TUG1 levels . The lncRNA ANRIL rs2383207 increased the risk of IS by 1.52-fold under the recessive model . Furthermore, the rs217727 TT and rs4929984 AA in the lncRNA H19 increased the risk of IS, with adjusted OR of 4.288, 3.020, respectively . Those studies provided a new perspective on the genetic mechanism of IS. Given above, we hypothesized that the MALAT1 SNPs were associated with IS risk. Our results supported the above assumption. As shown in Table 3, case-control studies indicated the rs1194338 A allele, AC and AA genotype of MALAT1 contributed to decreasing risk of IS. Additionally, the ACAG haplotype increased risk of IS (Table 4). Logistic regression also manifested the effect of the rs1194338 AC/AA on risk of IS (Table 5).
The rs1194338, a functional site, located in the promoter region of the MALAT1. Recently, several studies indicated the relationship between rs1194338 variant and human diseases. In hepatocellular carcinoma (HCC), female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion and a higher Child-Pugh grade, respectively . This suggested there was an interactive function between rs1194338 and the environment. Whether the rs1194338 interacts with the environment in IS remains to be further explored. In colorectal cancer, previous studies found carriers with AA and AC genotype of the rs1194338 were lower risk than CC genotype, and the conclusion from Li’s study showed no statistically significant difference in expression of MALAT1 between CC and AA genotype at rs1194338 [35, 36]. However, the GTEx database showed rs1194338 SNPs had differences in expression of MALAT1. Particularly, the AA genotype of rs1194338 significantly increased expression of MALAT1 compared to the CC genotype in brain-hippocampus and cerebellar hemisphere tissues (P<0.001) (Figure 1). Based on the above background, we speculated that the rs1194338 AC/AA genotype might increase the expression of MALAT1, which activated related pathways such as PI3K/AKT, thereby decreasing the risk of IS. Further studies are needed to investigate the correlation between the rs1194338 SNPs and expression of MALAT1 and the precise mechanism of rs1194338 SNPs in IS.
To our knowledge, the study of rs600231 A>G variant with risk of diseases have been rarely reported, but rs4102217 and rs591291 SNPs were evaluated in diseases. Zhang et al. indicated rs4102217 and rs591291 SNPs were not associated with susceptibility of rheumatoid arthritis . The Study of association with HCC have shown rs4102217 had a 1.32-fold risk in the dominant model, and rs591291 highlighted better prognosis in female and HBV negative subgroups, but association between MALAT1 haplotype (rs4102217-rs591291-rs11227209- rs619586) and HCC risk were not observed . In our study, we found that the ACAG haplotype had a 1.3-fold risk of IS although SNPs (rs600231, rs4102217, rs591291) did not correlate with the susceptibility of IS. It is well known that alteration in blood lipid levels is one of the risk factors in atherosclerotic plaques formation. Atherosclerotic plaques caused easily hypoxia, and possibly resulted in severe diseases such as ischemic stroke . According to the report, MALAT1 was involved in lipid metabolism . Thus, we further analyzed the relationship between the SNPs of MALAT1 and blood lipid levels in IS patients. Unfortunately, we failed to observe the significant association. These findings will help improve our understanding of the role of MALAT1 genetic variants in the pathogenesis of IS.
Although the results we got were promising, limitations still remained. Firstly, a relatively small sample may limit the authenticity of the statistical analysis. Secondly, our study is hospital-based case-control study, and potential selection bias may exist. In addition, the population we studied came from the southwest of China. There are distribution differences in polymorphisms of the same locus among different races according to the 1000 Genomes Project Data. Therefore, larger sample sizes from other medical centers of different races and ethnicities are needed to further confirm the role of MALAT1 SNPs in IS susceptibility. Finally, the effects of MALAT1 SNPs on IS are very interesting, but its mechanism is unclear. Both RNA and DNA should be collected simultaneously from the same samples to further verify the effects of SNPs on expression of MALAT1.