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Functional Polymorphisms in Pre-Mir146a and Pre-Mir499 Are www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 54), pp: 91876-91886 Research Paper Functional polymorphisms in pre-miR146a and pre-miR499 are associated with systemic lupus erythematosus but not with rheumatoid arthritis or Graves’ disease in Mexican patients Isidro Alemán-Ávila1,2, Mayra Jiménez-Morales1, Olga Beltrán-Ramírez1, Rosa Elda Barbosa-Cobos3, Silvia Jiménez-Morales4, Fausto Sánchez-Muñoz5, Guillermo Valencia-Pacheco6, Luis M. Amezcua-Guerra5, Yaneli Juárez-Vicuña5, Dulce Milagro Razo-Blanco Hernández7, María Concepción Aguilera-Cartas8, Ricardo F. López-Villanueva9, Oscar Peralta-Zaragoza10, Carlos Tovilla-Zárate11 and Julian Ramírez-Bello1 1Endocrine and Metabolic Disease Unit Research, Hospital Juarez of Mexico, Mexico City, Mexico 2Superior School of Medicine Postgraduate Program, National Polytechnic Institute, Mexico City, Mexico 3Rheumatology Department, Hospital Juarez of Mexico, Mexico City, Mexico 4Laboratory of Cancer Genomics, National Institute of Genomic Medicine, Mexico City, Mexico 5Immunology Department, National Institute of Cardiology, Mexico City, Mexico 6Hematology Laboratory, Regional Research Center, Autonomous University of Yucatan, Yucatan, Mexico 7Research Direction, Hospital Juarez of Mexico, Mexico City, Mexico 8Endocrinology Department, Hospital Juarez of Mexico, Mexico City, Mexico 9Rheumatology Department, Regional Hospital General (ISSSTE), Health Service Yucatan, Yucatan, Mexico 10 Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Cuernavaca, México 11Multidisciplinary Academic Division of Comalcalco, Juarez Autonomous University of Tabasco, Comalcalco, Mexico Correspondence to: Julian Ramírez-Bello, email: [email protected] Keywords: systemic lupus erythematosus, rheumatoid arthritis, Graves’ disease, microRNA gene, susceptibility Received: December 21, 2016 Accepted: June 30, 2017 Published: July 27, 2017 Copyright: Alemán-Ávila et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Recently, different microRNA (miRNA) gene polymorphisms have been evaluated in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves’ disease (GD). In the present study, we examined three single-nucleotide polymorphisms (SNPs) located in the pre-miR-146a (rs2910164G/C), pre-miR- 196a-2 (rs11614913C/T), and pre-miR-499 (rs3746444A/G) genes. Our study population included 900 Mexican patients with RA, SLE, or GD, as well as 486 healthy control individuals with no family history of inflammatory or autoimmune diseases. Genotyping was performed using TaqMan probes and a 5′ exonuclease assay. None of the investigated SNPs were associated with RA or GD susceptibility under any genetic model (co-dominant, recessive, or dominant). Genotype and allele frequencies of the miR-196a-2 rs11614913C/T polymorphism were similar between SLE cases and controls. In contrast, the miR-146a rs2910164G/C and miR-499 rs3746444A/G polymorphisms were associated with SLE susceptibility. These SNPs were not associated with lupus nephritis (LN). Our results suggest that polymorphisms in miR-146a, miR-196a-2, and miR-499 are not associated with RA or GD susceptibility. This is the first report documenting that the miR-146a rs2910164G/C and miR-499 rs3746444 polymorphisms are associated with SLE susceptibility but not with LN. www.impactjournals.com/oncotarget 91876 Oncotarget INTRODUCTION untranslated region (3′UTR) of target messenger RNAs (mRNAs), thus preventing their translation into proteins Autoimmune diseases (AIDs) constitute a [22–25]. heterogeneous group of pathologies characterized by loss Various miRNAs play important roles in regulating a of immunological tolerance, production of autoantibodies, wide array of biological functions, including proliferation, and increased expression of cytokines with inflammatory apoptosis, differentiation, immune response, and activity [1]. In the United States, AIDs affect about 5–8% inflammation [22–27]. With regards to AIDs, miR-146a of the general population, with most showing a higher is abnormally expressed in RA-affected tissues, including prevalence in women than in men [2]. Rheumatoid synovial fibroblasts, synovial tissue, serum, and peripheral arthritis (RA) is a chronic inflammatory autoimmune blood mononuclear cells (PBMCs) [28–33]. This miRNA disease characterized by synovial inflammation, which also shows abnormal expression in PBMCs and monocytes leads to joint tissue destruction and functional disability from SLE patients [33, 34], and in PBMCs from patients [3]. Systemic lupus erythematosus (SLE) is the prototype with Graves’ ophthalmopathy (GO). Moreover, patients of a multi-systemic AID, and is characterized by loss with active GO show lower serum miR-146a levels of immunological tolerance against self-antigens and than those with inactive GO [35, 36]. Both miR-196a production of pathogenic autoantibodies, ultimately and miR-499 are thought to be involved in autoimmune resulting in damage to multiple organ systems [4]. Graves’ and inflammatory diseases, because they promote the diseases (GD) is an organ-specific AID, in which the expressions of several relevant proteins, including major antigenic target is the thyroid-stimulating hormone interleukin (IL)-23a, IL-6, IL-2, C-reactive protein, IL- receptor (TSHR). TSHR-autoantibodies bind to TSHR, 18R, and IL-2R. Thus, both miRNAs could potentially mimicking the action of its ligand (TSH) and causing contribute to the pathogenesis and disease progression of hyperthyroidism [5]. several AIDs [37–39]. Although the etiologies of RA, SLE, and GD Functional SNPs located in miRNA genes (miR- remain unclear, the identified risk factors include gender; SNPs) could potentially affect pri-miRNA transcription genetic background; and environmental agents, such or pri-miRNA/pre-miRNA processing, or could disrupt as geography, climate, endemic microbes, and socio- miRNA–mRNA interactions if located in the mature cultural practices, including smoking, lifestyle, and miRNA sequence or in miRNA binding sites [40–42]. dietary habits [6–7]. Investigations using a candidate The functional miR-SNP rs2910164G/C, located in gene approach and genome-wide association studies pre-miR-146a, has been evaluated in RA patients from have demonstrated that RA, SLE, and GD susceptibility different populations, yielding controversial results. is conferred by different variants of protein-coding Yang et al. [11], Hashemi et al. [12], and El-Shal et al. genes, including HLA-class II, PTPN22, TNFAIP3, [13] reported that this polymorphism was not associated STAT4, TNFRSF14, BLK, and TRAF1 [8–10]. Genetic with RA susceptibility; however, Zhou et al. [43] found risk factors for these AIDs may also include single- that the GG genotype was significantly associated with nucleotide polymorphisms (SNPs) in non-coding RNA RA among women. This SNP has not been associated genes, including the microRNAs (miRNAs) 146a, miR- with SLE or GD susceptibility in patients from different 196a-2 and miR-499 [11–17]. populations [16, 44, 45]. Another functional miR- RNA polymerase II initially transcribes miRNA SNP, miR-499 rs3746444A/G, is reportedly associated genes, producing primary miRNAs (pri-miRNAs) of with RA susceptibility, severity, and disease activity approximately 2 kb in length. In the nucleus, these in Iranian and Egyptian populations, but not in a pri-miRNAs are processed by RNase III Drosha Chinese population [11–13, 46]. This polymorphism and the DiGeorge syndrome chromosomal region 8, also showed no association with SLE susceptibility in Microprocessor Complex Subunit (DGCR8; DiGeorge a Chinese population [44]; however, it was recently syndrome chromosomal region 8) protein, generating a found to be associated with GD susceptibility in a precursor miRNA (pre-miRNA) of approximately 100 Chinese population [16]. The functional miR-196a-2 bp. These pre-miRNAs are transported from the nucleus rs11614913C/T SNP has only been evaluated in Egyptian to the cytoplasm via exportin-5. In the cytoplasm, patients with RA, and no evidence of association was pre-miRNAs are cleaved by the RNase III enzyme detected [46]. Dicer, in complex with the human immunodeficiency In the present case-control study, we evaluated virus transactivating response RNA-binding protein whether the polymorphisms pre-miR-146a rs2910164G/C, (TRBP), ultimately forming small non-coding RNAs pre-miR-196a-2 rs11614913C/T, and pre-miR-499 of approximately 19–22 nucleotides, termed mature rs3746444A/G conferred risk for RA, SLE, and GD miRNAs [18–22]. Mature miRNAs function in the in a sample of Mexican patients. We also evaluated negative regulation of gene expression, acting at whether these polymorphisms were associated with lupus the post-transcriptional level by binding to the 3′ nephritis (LN). www.impactjournals.com/oncotarget 91877 Oncotarget RESULTS miR-499 rs3746444A/G polymorphisms in patients with RA, SLE, and GD [11–13, 16, 43–46]. Zhou et al. [43] Demographic features of cases and controls found that the GG genotype of miR-146a rs2910164G/C was significantly associated with RA among women. In This study included 900 patients with AIDs: 412 contrast, we found no association between this SNP and with RA (378 female, 34 male), 407 with SLE (384 female,
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