Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disorder affecting the peripheral joints. Different microRNAs had been investigated in RA including miRNA-146a meanwhile, miRNA-499 there were no studies to prove its expression in RA serum samples. This study was performed to investigate expression of both miRNAs-146a and -499 and their polymorphisms in Egyptian patients with RA and to evaluate their relationship with clinico-pathological data. The present study includes 108 subjects classified into two main groups: 52 RA patients and 56 unrelated healthy controls. RA patients were subclassified according to DAS28 score into inactive (23 patients) and active (29 patients). Quantitative expression of serum miRNA-146a, miRNA-499 as well as their Genotyping rs2910164 (C/G) and rs3746444 (T/C), respectively, were done to all subjects using real-time PCR. Serum miRNA-146a and -499 were significantly over expressed in RA patients, but they were not correlated to disease activity. Serum miRNA-146a was negatively correlated with anti-nuclear antibodies (ANA). miRNA-146a (rs2910164) genotyping revealed that the GG genotype and the frequency of the G allele were significantly higher in RA patients compared to the controls. miRNA-499 (rs3746444), genotyping revealed that the CC genotype and the frequency of the C allele were significantly higher. It can be concluded that both miRNAs-146a and -499 can be used as diagnostic markers for RA patients. Both miRNA-146a (rs2710164) and miRNA-499 (rs3746444) were significantly associated with RA susceptibility. The C allele of miRNA-146a (rs2710164) can be considered to be protective. On the other hand, the C allele of miRNA-499 (rs3746444) was significantly associated with RA susceptibility.
Similar content being viewed by others
References
Majithia V, Geraci SA (2007) Rheumatoid arthritis: diagnosis and management. Am J Med 120(11):936–939
Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 376(9746):1094–1108
De Rycke L, Peene I, Hoffman IE (2004) Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis. Ann Rheum Dis 63:158–161
Burmester GR, Feist E, Dörner T (2014) Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol 10(2):77–88
Latini A, Ciccacci C, Novelli G, Borgiani P (2017) Polymorphisms in miRNA genes and their involvement in autoimmune diseases susceptibility. Immunol Res 65(4):811–827
Janssens S, Beyaert R (2003) Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell 11(2):293–302
El-Shal AS, Aly NM, Galil SM, Moustafa MA, Kandel WA (2013) Association of microRNAs genes polymorphisms with rheumatoid arthritis in Egyptian female patients. Joint Bone Spine 80(6):626–631
Ciccacci C, Morganti R, Di Fusco D, D’Amato C, Cacciotti L, Greco C, Rufini S, Novelli G, Sangiuolo F, Marfia GA, Borgiani P, Spallone V (2014) Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes. Acta Diabetol 51(4):663–671
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588
Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38(1):44–48
Chandrashekara S, Shobha V, Dharmanand BG, Jois R, Kumar S et al (2017) Comorbidities and related factors in rheumatoid arthritis patients of south India-Karnataka Rheumatoid Arthritis Comorbidity (KRAC) study. Reumatismo 69(2):47–58
Cutolo M, Villaggio B, Craviotto C, Pizzorni C, Seriolo B, Sulli A (2002) Sex hormones and rheumatoid arthritis. Autoimmun Rev 1(5):284–289
Fransen J, Creemers MC, Van Riel PL (2004) Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology 43(10):1252–1255
Lai X, Wang H, Cao J, Li Y, Dai Y, Xiang Y, Zhang L (2016) Circulating IL-27 is elevated in rheumatoid arthritis patients. Molecules 21(11):E1565
Van den Berg WB (2001) Uncoupling of inflammatory and destructive mechanisms in arthritis. Semin Arthritis Rheum 30(2):7–16
Syed KM, Pinals RS (1996) leukocytosis in rheumatoid arthritis. J Clin Rheumatol 2(4):197–202
Richardson MP, Ayliffe MJ, Helbert M, Davies EG (1998) A simple flow-cytometry assay using dihydrorhodamine for the measurement of the neutrophil respiratory burst in whole blood: comparison with the quantitative nitrobluetetrazolium test. J Immunol Methods 219(1–2):187–193
Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK (2008) Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 10:R101
Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M, Asahara H (2008) Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58:1284–1292
Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486
Rusca N, Monticelli S (2011) MiR-146a in immunity and disease. Mol Biol Int 2011:437301
Chan EKL, Ceribelli A, Satoh M (2013) MicroRNA-146a in autoimmunity and innate immune responses. Ann Rheum Dis 72(2):ii90–ii95
Churov AV, Oleinik EK, Knip M (2015) MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun Rev 14:1029–1037
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY (2010) Function of miR-146a in controlling treg cell-mediated regulation of Th1 responses. Cell 142(6):914–929
Stanczyk J, Pedrioli DML, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, Detmar M, Gay S, Kyburz D (2008) Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58(4):1001–1009
Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, Deie M, Suzuki O, Adachi N, Ochi M (2010) MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord 58(4):1001–1009
Abou-Zeid A, Saad M, Soliman E (2011) MicroRNA 146a expression in rheumatoid arthritis: association with tumor necrosis factor-alpha and disease activity. Genet Test Mol Biomark 15(11):807–812
Elsayed HM, Khater WS, Ibrahim AA, Hamdy MS, Morshedy NA (2017) MicroRNA-146a expression as a potential biomarker for rheumatoid arthritis in Egypt. Egypt J Med Hum Genet 18:173–179
Wang H, Peng W, Ouyang X, Li W, Dai Y (2012) Circulating microRNAs as candidate biomarkers in patients with systemic lupus erythematosus. Transl Res 160(3):198–206
Yang B, Chen J, Li Y, Zhang J, Li D, Huang Z, Cai B, Li L, Shi Y, Ying B, Wang L (2012) Association of polymorphisms in pre-miRNA with inflammatory biomarkers in rheumatoid arthritis in the Chinese Han population. Hum Immunol 73:101–106
Li K, Tie H, Hu N, Chen H, Yin X, Peng C, Wan J, Huang W (2014) Association of two polymorphisms rs2910164 in miRNA-146a and rs3746444 in miRNA-499 with rheumatoid arthritis: a meta-analysis. Hum Immunol 75:602–608
Huszar JM, Payne CJ (2014) MIR146A inhibits JMJD3 expression and osteogenic differentiation in human mesenchymal stem cells. FEBS Lett 588(9):1850–1856
Jing D, Hao J, Shen Y, Tang G, Li M, Huang S, Zhao Z (2015) The role of microRNAs in bone remodeling. Int J Oral Sci 7(3):131–143
Sethupathy P, Collins FS (2008) MicroRNA target site polymorphisms and human disease. Trends Genet 24:489–497
Chatzikyriakidou A, Voulgari PV, Georgiou I, Drosos AA (2012) miRNAs and related polymorphisms in rheumatoid arthritis susceptibility. Autoimmun Rev 11(9):636–641
Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A (2008) Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA 105:7269–7274
Chatzikyriakidou A, Voulgari PV, Georgiou I, Drosos AA (2010) A polymorphism in the 30-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility. Joint Bone Spine 77:411–413
Zhou X, Zhu J, Zhang H, Zhou G, Huang Y, Liu R (2015) Is the microRNA-146a (rs2910164) polymorphism associated with rheumatoid arthritis? Association of microRNA-146a (rs2910164) polymorphism and rheumatoid arthritis could depend on gender. Joint Bone Spine 82(3):166–171
Hashemi M, Eskandari-Nasab E, Zakeri Z, Atabaki M, Bahari G, Jahantigh M, Taheri M, Ghavami S (2013) Association of pre-miRNA-146a rs2910164 and pre-miRNA-499 rs3746444 polymorphisms and susceptibility to rheumatoid arthritis. Mol Med Rep 7:287–291
Hassine HB, Boumiza A, Sghiri R, Baccouche K, Boussaid I, Atig A, Shakoor Z, Bouajina E, Zemni R (2017) C allele of miR-146a rs2910164 was found to be protective from RA. Micro RNA-146a But Not IRAK1 is associated with rheumatoid arthritis in the Tunisian population. Genet Test Mol Biomark 21(2):92–96
Toraih EA, Ismail NM, Toraih AA, Hussein MH, Fawzy MS (2016) Precursor miR-499a variant but not miR-196a2 is associated with rheumatoid arthritis susceptibility in an Egyptian population. Mol Diagn Ther 20(3):279–295
Yang B, Zhang JL, Shi YY, Li DD, Chen J, Huang ZC (2011) Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis in a Han Chinese population. Mol Biol Rep 38:4913–4919
Fattah SA, Ghattas MH, Saleh SM, Abo-Elmatty DM (2017) Pre-micro RNA-499 gene polymorphism rs3746444 T/C is associated with susceptibility to rheumatoid arthritis in Egyptian population. Ind J Clin Biochem. https://doi.org/10.1007/s12291-017-0652-7
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest to disclose.
Ethical approval
The study was conducted on patients with RA. This study was approved by the Ethical Committee of Kasr Al Ainy Medical Hospital and was in accordance with the principle of Helsinki Declaration.
Informed consent
A written informed consent was obtained from each participant.
Rights and permissions
About this article
Cite this article
Ayeldeen, G., Nassar, Y., Ahmed, H. et al. Possible use of miRNAs-146a and -499 expression and their polymorphisms as diagnostic markers for rheumatoid arthritis. Mol Cell Biochem 449, 145–156 (2018). https://doi.org/10.1007/s11010-018-3351-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-018-3351-7