miR-21 (rs1292037) SNP was determined in 250 T1DM patients and 250 population-matched controls. We report a significant association between the miR-21 rs1292037 T/C genotype and the incidence of T1DM. It was also found that miR-21 is significantly overexpressed in T1DM patients comparing to the control group. Moreover, this study demonstrated that miR-21 was significantly upregulated in subjects with the T/C genotype.
MiRNAs, as regulators of gene expression, are seen to contribute to several pathological conditions including T1DM (18). SNPs in the miRNAs coding gene are reported to affect the biological function of these non-coding RNAs, which can lead to the incidence of numerous human diseases (19). Multiple studies have investigated the role of miRNAs-relates SNPs in the incidence and prognosis of T1DM. For instance, miR-196a rs11614913 is reported to be associated with the pathogenesis of T1DM (13). Moreover, studies have shown that SNPs in miRNAs coding genes can determine the development of pancreatic cells and insulin secretion. For instance, Wang et al. have detected a link between miR-124a rs531564 and miR-27a rs895819, and pancreatic development, adipocyte differentiation, and insulin secretion (20). It is observed that miR-21 targets genes that act in cell proliferation and cell apoptosis including Ras and Pdcd4 (21). SNPs in the miRNA coding genes are seen to affect the binding affinity and binding ability of miRNAs, which can consequently affect the expression of the miRNA target genes (9). Although miR-21 rs1292037 is seen to be correlated with the prognosis of hepatocellular carcinoma and cervical cancer, there is no reported evidence on the association of this reference SNP and T1DM (14, 22).
In addition to the critical role of miR-SNPs in the incidence and prognosis of autoimmune diseases such as T1DM, alteration in the expression level of miRNAs in autoimmune diseases is manifested by several researchers (23). In a research conducted by Mostahfezian et al., it is reported that miR-21 is upregulated in T1DM patients. They postulated that upregulated levels of miR-21 inhibit T cells apoptosis, which leads to autoimmunity (17). Compelling evidence has shown that upregulation of miR-21 can expose β cells to proinflammatory cytokines. This unfortunate phenomenon promotes cell death, which stimulates T1DM (24). Upregulation of miR-21 in T1DM patients is also reported by Fouad and their colleagues. Analyzing the plasma of T1DM patients, they tracked the upregulated levels of miR-21. Moreover, they claimed that in the first 5 years of the disease onset, when is even sooner than the development of microalbuminuria, upregulated levels of this miRNA can be detected (25).
Analyzing miRNAs expression level and/or miRNAs-related SNPs have been proposed as a biomarker in medicine and biotechnology for the early detection of diseases with genetic backgrounds (26, 27). Regarding T1DM, the early detection of this disease not only increases the quality of life in patients but also elevates the possibility of preventing T1DM complications such as heart disease, foot ulcer, retinopathy, and neuropathy (28). More importantly, early detection of T1DM can positively affect the honeymoon period (a transition remission phase after the commencement of insulin treatment that insulin doses can be significantly decreased or even totally withdrawn) (29). In this case, the specialists will be given more time to take considerable actions (e.g., adjunctive therapy) to prolong the reduction of residual β cell function in T1DM patients (30). Taken together, the results of this study suggest that miR-21 rs1292037 T/C genotype can be considered as a putative biomarker for early detection of T1DM. Moreover, analyzing miR-21 expression patterns can be also evaluated for this purpose.
Some limitations should be considered when the acquired data are analyzed. Firstly, this study included 250 T1DM patients and 250 control subjects, and therefore, expanded research with a larger case and control population is recommended. Secondly, this research was limited to the Iranian population, and the authors realize that there might be differences in this SNP in the T1DM characteristics of distinct populations. For this reason, we recommend further investigations into other ethnic/racial groups.