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

Farhad Tabasi,Mahmoud Ali Kaykhaei,Ahmad Alinaghi Langari,Pouria Pourzand,Gholamreza Bahari,Shamim Sarhadi,Mehrdad Heravi,Mohsen Taheri,Vahed Hasanpour,Saeid Ghavami,Mohammad Hashemi

doi:10.3390/ijms221810094

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.

Highlights

Hashimoto thyroiditis (HT) is an organ-specific autoimmune disease and the most prevalent type of autoimmune thyroid disease (AITD), characterized by immunocyte imbalance, autoantibodies production, and increased expression and activity of inflammatory mediators [1]
Significant roles for miRs have been demonstrated in several human diseases, including autoimmune disorders
Significant roles for miRs have in several human diseases, immune system activity, and their dysfunction is closely associated withinautoimmune including autoimmune disorders

Summary

Introduction

Hashimoto thyroiditis (HT) is an organ-specific autoimmune disease and the most prevalent type of autoimmune thyroid disease (AITD), characterized by immunocyte imbalance, autoantibodies production, and increased expression and activity of inflammatory mediators [1]. With a prevalence of 4.5% (both clinical and subclinical cases) based on biochemical assessments, HT is the most common cause of spontaneous hypothyroidism in areas with sufficient iodine intake; of note, the prevalence of HT determined by cytological diagnosis is even higher and estimated to reach 13.4% [2]. 4% of cases with subclinical hypothyroidism develop overt hypothyroidism, a risk that increases with age [2]. HT is characterized by epithelial cell destruction, diffuse infiltration of lymphocytic cells, fibrosis, and higher thyroid autoantibodies [2]. Known as a multifactorial disease, accumulating evidence emphasizes the role of genetic predisposition in HT [4,5]

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Conclusion