Association of miR-499 Polymorphism and Its Regulatory Networks with Hashimoto Thyroiditis Susceptibility: A Population-Based Case-Control Study

Abstract

Hashimoto thyroiditis (HT) is a common autoimmune disorder with a strong genetic background. Several genetic factors have been suggested, yet numerous genetic contributors remain to be fully understood in HT pathogenesis. MicroRNAs (miRs) are gene expression regulators critically involved in biological processes, of which polymorphisms can alter their function, leading to pathologic conditions, including autoimmune diseases. We examined whether miR-499 rs3746444 polymorphism is associated with susceptibility to HT in an Iranian subpopulation. Furthermore, we investigated the potential interacting regulatory network of the miR-499. This case-control study included 150 HT patients and 152 healthy subjects. Genotyping of rs3746444 was performed by the PCR-RFLP method. Also, target genomic sites of the polymorphism were predicted using bioinformatics. Our results showed that miR-499 rs3746444 was positively associated with HT risk in heterozygous (OR = 3.32, 95%CI = 2.00–5.53, p < 0.001, CT vs. TT), homozygous (OR = 2.81, 95%CI = 1.30–6.10, p = 0.014, CC vs. TT), dominant (OR = 3.22, 95%CI = 1.97–5.25, p < 0.001, CT + CC vs. TT), overdominant (OR = 2.57, 95%CI = 1.62–4.09, p < 0.001, CC + TT vs. CT), and allelic (OR = 1.92, 95%CI = 1.37–2.69, p < 0.001, C vs. T) models. Mapping predicted target genes of miR-499 on tissue-specific-, co-expression-, and miR-TF networks indicated that main hub-driver nodes are implicated in regulating immune system functions, including immunorecognition and complement activity. We demonstrated that miR-499 rs3746444 is linked to HT susceptibility in our population. However, predicted regulatory networks revealed that this polymorphism is contributing to the regulation of immune system pathways.