Original Article

Polymorphisms of Pre-miR-499 rs3746444 T/C and Pre-miR-146a rs2910164 C/G in the Autoimmune Diseases of Rheumatoid Arthritis and Systemic Lupus Erythematosus in the West of Iran


Background: The present research is a case-control study to analyze the influence of pre-miRNA-146a rs2910164 and pre‑miRNA-499 rs3746444 polymorphisms as candidate susceptibility factors for both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

Methods: Polymorphism in miR146 and miR499 using ARMS-PCR was genotyped on 139 autoimmune disease (AD) patients (89 RA and 50 SLE) referred to Educational Hospitals of Khorramabad, Lorestan Province, west of Iran in 2018–2019 and 237 healthy control subjects.

Results: A significant increase in the likelihood of carrying the GC vs. GG of pre-miR146-rs2910164 and T vs C allele of pre-miR499- rs3746444 in patients with RA was found. On the contrary, patients with RA were less likely to carry the TC + CC vs TT genotype and the C vs T allele of pre-miR499- rs374644. In females with the GC vs GG and GC+ CC vs GG genotypes, a significant association was found with the increased risk of RA. Interestingly, the genotypic combination of TC of the pre-miR499-rs374644 with GG of pre-miR146-rs2910164 more strongly decreased the risk of RA. In patients with SLE, no notable associations were found between both pre-miRNA-146a rs2910164 and pre‑miRNA-499 rs3746444 with risk of disease.

Conclusion: Genetic polymorphisms of miR146 rs2910164 is associated with RA susceptibility especially in females. Interestingly, there is a potential in miR499 to reduce the risk with the protective effect of gene-gene interactions on miR146 in RA disease.

Anaya J, Shoenfeld Y, Correa P, García-Carrasco M, Cervera R (2005). Autoinmunidad y enfermedad autoinmune. Medellín: Corporación para Investigaciones Biológicas, 515-22.

Geng H, Tan X-D (2016). Functional diversity of long non-coding RNAs in immune regulation. Gen & disea 3: 72-81.

Oner T, Yenmis G, Tombulturk K, Cam C, Kucuk OS, Yakicier MC, Dizman D, Sultuybek GK (2015). Association of pre-miRNA-499 rs3746444 and pre-miRNA-146a rs2910164 polymorphisms and susceptibility to Behcet's disease. Genet Test Mol Biomarkers, 19: 424-30.

Whitacre CC (2001). Sex differences in autoimmune disease. Nature Immunol, 2 :777.

Ngo S, Steyn F, McCombe P (2014). Gender differences in autoimmune disease. Front Neuroendocrinol, 35: 347-69.

Fairweather D, Frisancho-Kiss S, Rose NR (2008). Sex differences in autoimmune disease from a pathological perspective. ‎Am J Pathol 173: 600-9.

Rusca N, Monticelli S (2011) MiR-146a in immunity and disease. Mol Biol Int, 2011.

Cammaerts S, Strazisar M, De Rijk P, Del Favero J (2015). Genetic variants in microRNA genes: impact on microRNA expression, function, and disease. Front Genet, 6: 186.

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: 287-91.

Ji J, Cha E, Lee W(2014). Association of miR-146a polymorphisms with systemic lupus erythematosus: a meta-analysis. Lupus 23: 1023-30.

Luo X , Yang W, Ye DQ, Cui H, Zhang Y, Hirankarn N, Qian X, Tang Y, Lau YL, de Vries N, Tak PP, Tsao BP, Shen N (2011) A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus. PLoS Genet, 7: e1002128.

Zhang J , Yang B, Ying B, Li D, Shi Y, Song X, Cai B, Huang Z, Wu Y, Wang L (2011). Association of pre-microRNAs genetic variants with susceptibility in systemic lupus erythematosus. Mol Biol Rep, 38: 1463-8.

Löfgren SE , Frostegård J, Truedsson L, Pons-Estel BA, D'Alfonso S, Witte T, Lauwerys BR, Endreffy E, Kovács L, Vasconcelos C, Martins da Silva B, Kozyrev SV, Alarcón-Riquelme ME (2012). Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun, 13: 268.

Jiménez-Morales S, Gamboa-Becerra R, Baca V, Del Río-Navarro BE, López-Ley DY, Velázquez-Cruz R, Saldaña-Alvarez Y, Salas-Martínez G, Orozco L (2012). MiR‐146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients. HLA, 80: 317-21

Alemán-Ávila I, Jiménez-Morales M, Beltrán-Ramírez O, Barbosa-Cobos RE, Jiménez-Morales S, Sánchez-Muñoz F, Valencia-Pacheco G, Amezcua-Guerra LM, Juárez-Vicuña Y, Razo-Blanco Hernández DM, Aguilera-Cartas MC, López-Villanueva RF, Peralta-Zaragoza O, Tovilla-Zárate C, Ramírez-Bello J (2017). 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. Oncotarget , 8: 91876.

Fu L , Jin L , Yan L , Shi J , Wang H , Zhou B , Wu X (2016). Comprehensive review of genetic association studies and meta-analysis on miRNA polymorphisms and rheumatoid arthritis and systemic lupus erythematosus susceptibility. Hum immunol, 77: 1-6.

Yang B , Zhang JL, Shi YY, Li DD, Chen J, Huang ZC, Cai B, Song XB, Li LX, Ying BW, Wang LL. (2011). Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis in a Han Chinese population. Mol Biol Rep, 38: 4913-9.

Iwai N, Naraba H (2005). Polymorphisms in human pre-miRNAs. Biochem Biophys Res Commun, 331: 1439-44.

Hu Z , Liang J, Wang Z, Tian T, Zhou X, Chen J, Miao R, Wang Y, Wang X, Shen H (2009). Common genetic variants in pre‐microRNAs were associated with increased risk of breast cancer in Chinese women. Hum muta, 30: 79-84.

Jing L, Su L, Ring BZ (2014). Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review. PloSOne 9: e97522.

Li C , Fu W , Zhang Y , Zhou L , Mao Z, Lv W, Li J, Zhou Y (2015). Meta-analysis of microRNA-146a rs2910164 G> C polymorphism association with autoimmune diseases susceptibility, an update based on 24 studies. PloSOne, 10: e0121918.

Yang Y, Zhang K, Zhou R (2014). Meta-analysis of pre-miRNA polymorphisms association with susceptibility to autoimmune diseases. Immunol Invest, 43 :13-27.

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: 602-8.

Pauley KM, Cha S, Chan EK (2009) MicroRNA in autoimmunity and autoimmune diseases. J Autoimmun 32: 189-94.

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, 105: 7269-74.

Chen J-Q, Papp G, Szodoray P, Zeher M (2016). The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev 15: 1171-80.

Yue C, Wang M, Ding B, Wang W, Fu S, Zhou D, Zhang Z, Han S (2011). Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population. Gynecol Oncol, 122: 33-7.

Taganov KD, Boldin MP, Chang K-J, 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, 103:12481-6.

Wei WJ, Wang YL, Li DS, Wang Y, Wang XF, Zhu YX, Yang YJ, Wang ZY, Ma YY, Wu Y, Jin L, Ji QH, Wang JC (2013). Association between the rs2910164 polymorphism in pre-Mir-146a sequence and thyroid carcinogenesis PloSOne, 8:e56638.

Arena A, Iyer AM, Milenkovic I, Kovacs GG, Ferrer I, Perluigi M, Aronica E (2017). Developmental expression and dysregulation of miR-146a and miR-155 in Down's syndrome and mouse models of Down's syndrome and Alzheimer's disease. ‎Curr Alzheimer Res, 14:1305-17.

Jazdzewski K, Liyanarachchi S, Swierniak M, Pachucki J, Ringel MD, Jarzab B, de la Chapelle A (2009). Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Natl Acad Sci USA, 106 :1502-5.

Amal S, Aly NM, Galil SMA, Moustafa MA, Kandel WA (2013). Association of microRNAs genes polymorphisms with rheumatoid arthritis in Egyptian female patients. Joint Bone Spine, 80 :626-31.

Lee YH, Bae S-C, Choi SJ, Ji JD, Song GG (2012). Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep, 39:81-7.

uan FL, Hu W, Lu WG, Li X, Li JP, Xu RS, Li CW, Chen FH, Jin C (2011). Targeting interleukin-21 in rheumatoid arthritis. Mol Biol Rep, 38:1717-21.

IssueVol 49 No 4 (2020) QRcode
SectionOriginal Article(s)
MicroRNA polymorphisms; Rheumatoid arthritis; Systemic lupus erythematosus

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How to Cite
AHMADI K, SOLEIMANI A, SOLEIMANI MOTLAGH S, BAHARVAND AHMADI S, ALMASIAN5M, KIANI AA. Polymorphisms of Pre-miR-499 rs3746444 T/C and Pre-miR-146a rs2910164 C/G in the Autoimmune Diseases of Rheumatoid Arthritis and Systemic Lupus Erythematosus in the West of Iran. Iran J Public Health. 2020;49(4):782-790.