Skip to main content
SpringerLink
Log in

Association of the miR-196a2, miR-146a, and miR-499 Polymorphisms with Asthma Phenotypes in a Korean Population

  • Original Research Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Background

MicroRNAs (miRNAs) modulate expressions of inflammatory genes, thereby regulating inflammatory responses. Single nucleotide polymorphisms (SNPs) in miRNAs could affect their efficiency in binding to messenger RNAs (mRNAs).

Objective

We investigated the associations of miRNA SNPs with asthma phenotypes. miR-196a2 (rs11614913 T>C), miR-146a (rs2910164 C>G), and miR-499 (rs3746444 A>G) were genotyped in 347 asthma patients and 172 normal healthy controls (NCs).

Results

The CT/CC genotype of miR-196a2 rs11614913 was associated with eosinophilic asthma (p = 0.004) and a higher sputum eosinophil count compared with the TT genotype (p = 0.003). The CG/GG genotype of miR-146a rs2910164 tended to be associated with higher bronchial hyperresponsiveness to methacholine (PC20) compared with the CC genotype. The AG/GG genotype of miR-499 rs3746444 was associated with higher predicted values of forced expiratory volume in 1 s (%FEV1) compared with the AA genotype (p = 0.008).

Conclusions

Genetic polymorphisms in miR-196a2, miR-146a, and miR-499 could be potential biomarkers for asthma phenotypes and targets for asthma treatments in a Korean population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Grainge C, Thomas PS, Mak JC, Benton MJ, Lim TK, Ko FW. Year in review 2015: asthma and chronic obstructive pulmonary disease. Respirology (Carlton, VIC). 2016;21:765–75.

    Article  Google Scholar 

  2. Rusca N, Monticelli S. MiR-146a in immunity and disease. Mol Biol Int. 2011;2011:437301.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R et al. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediat Inflamm. 2015;2015:879783.

  4. Erle DJ, Sheppard D. The cell biology of asthma. J Cell Biol. 2014;205:621–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Williams AE, Larner-Svensson H, Perry MM, Campbell GA, Herrick SE, Adcock IM, et al. MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy. PLoS One. 2009;4:e5889.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pua HH, Ansel KM. MicroRNA regulation of allergic inflammation and asthma. Curr Opin Immunol. 2015;36:101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sonkoly E, Ståhle M, Pivarcsi A, editors. MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation. Semin Cancer Biol. 2008;18:131–40.

  8. Liu Z, Zhang XH, Callejas-Diaz B, Mullol J. MicroRNA in United Airway diseases. Int J Mol Sci. 2016;17:716.

  9. Sonkoly E, Pivarcsi A. MicroRNAs in inflammation. Int Rev Immunol. 2009;28:535–61.

    Article  CAS  PubMed  Google Scholar 

  10. Midyat L, Gulen F, Karaca E, Ozkinay F, Tanac R, Demir E, et al. MicroRNA expression profiling in children with different asthma phenotypes. Pediatr Pulmonol. 2016;51:582–7.

    Article  PubMed  Google Scholar 

  11. Qin HB, Xu B, Mei JJ, Li D, Liu JJ, Zhao DY, et al. Inhibition of miRNA-221 suppresses the airway inflammation in asthma. Inflammation. 2012;35:1595–9.

    Article  CAS  PubMed  Google Scholar 

  12. Haj-Salem I, Fakhfakh R, Berube JC, Jacques E, Plante S, Simard MJ, et al. MicroRNA-19a enhances proliferation of bronchial epithelial cells by targeting TGFβR2 gene in severe asthma. Allergy. 2015;70:212–9.

    Article  CAS  PubMed  Google Scholar 

  13. Su XW, Yang Y, Lv ML, Li LJ, Dong W, Gao LB, et al. Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population. DNA Cell Biol. 2011;30:919–23.

    Article  CAS  PubMed  Google Scholar 

  14. Jiménez-Morales S, Gamboa-Becerra R, Baca V, Río-Navarro D, López-Ley D, Velázquez-Cruz R, et al. miR-146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients. Tissue Antigens. 2012;80:317–21.

    Article  PubMed  Google Scholar 

  15. Hussein MH, Toraih EA, Aly NM, Riad E, Fawzy MS. A passenger strand variant in miR-196a2 contributes to asthma severity in children and adolescents: a preliminary study. Biochem Cell Biol. 2016;94:347–57.

  16. Szymczak I, Wieczfinska J, Pawliczak R. Molecular background of miRNA role in asthma and COPD: an updated insight. Biomed Res Int. 2016;2016:7802521.

  17. Min KT, Kim JW, Jeon YJ, Jang MJ, Chong SY, Oh D, et al. Association of the miR-146aC>G, 149C>T, 196a2C>T, and 499A>G polymorphisms with colorectal cancer in the Korean population. Mol Carcinog. 2012;51(Suppl 1):E65–73.

    Article  CAS  PubMed  Google Scholar 

  18. Park YS, Jeon YJ, Lee BE, Kim TG, Choi JU, Kim DS, et al. Association of the miR-146aC>G, miR-196a2C>T, and miR-499A>G polymorphisms with moyamoya disease in the Korean population. Neurosci Lett. 2012;521:71–5.

    Article  CAS  PubMed  Google Scholar 

  19. Kim YR, Hong SH. Associations of microRNA polymorphisms (miR-146a, miR-196a2, and miR-499) with the risk of hypertension in the Korean population. Genet Test Mol Biomark. 2016;20:420–6.

    Article  CAS  Google Scholar 

  20. Lim JJ, Shin DA, Jeon YJ, Kumar H, Sohn S, Min HS, et al. Association of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with ossification of the posterior longitudinal ligament of the cervical spine. PLoS One. 2016;11:e0159756.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Global Initiative for Asthma. Global strategy for asthma management and prevention (updated 2015). http://www.ginasthma.org. Accessed 15 March 2016

  22. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–73.

  23. Kim SH, Bae SJ, Palikhe S, Ye YM, Park HS. Effects of MBL2 polymorphisms in patients with diisocyanate-induced occupational asthma. Exp Mol Med. 2015;47:e157.

    Article  CAS  PubMed  Google Scholar 

  24. Ban GY, Pham D, Trinh T, Lee SI, Suh DH, Yang EM, et al. Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target. Clin Exp Allergy. 2016;46:48–59.

    Article  CAS  PubMed  Google Scholar 

  25. Walford HH, Doherty TA. Diagnosis and management of eosinophilic asthma: a US perspective. J Asthma Allergy. 2014;7:53–65.

    PubMed  PubMed Central  Google Scholar 

  26. Perry MM, Moschos SA, Williams AE, Shepherd NJ, Larner-Svensson HM, Lindsay MA. Rapid changes in microRNA-146a expression negatively regulate the IL-1-induced inflammatory response in human lung alveolar epithelial cells. J Immunol. 2008;180:5689–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Toraih EA, Ismail NM, Toraih AA, Hussein MH, Fawzy MS. Precursor miR-499a variant but not miR-196a2 is associated with rheumatoid arthritis susceptibility in an Egyptian population. Mol Diagn Ther. 2016;20:279–95.

    Article  CAS  PubMed  Google Scholar 

  28. Liu CJ, Tsai MM, Tu HF, Lui MT, Cheng HW, Lin SC. miR-196a overexpression and miR-196a2 gene polymorphism are prognostic predictors of oral carcinomas. Ann Surg Oncol. 2013;20(Suppl 3):S406–14.

    Article  PubMed  Google Scholar 

  29. Luthra R, Singh RR, Luthra MG, Li YX, Hannah C, Romans AM, et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene. 2008;27:6667–78.

    Article  CAS  PubMed  Google Scholar 

  30. Hou T, Ou J, Zhao X, Huang X, Huang Y, Zhang Y. MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1. Br J Cancer. 2014;110:1260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tian T, Shu Y, Chen J, Hu Z, Xu L, Jin G, et al. A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomark. 2009;18:1183–7.

    Article  CAS  Google Scholar 

  32. Hoffman AE, Zheng T, Yi C, Leaderer D, Weidhaas J, Slack F, et al. MicroRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res. 2009;69:5970–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li LJ, Gao LB, Lv ML, Dong W, Su XW, Liang WB, et al. Association between SNPs in pre-miRNA and risk of chronic obstructive pulmonary disease. Clin Biochem. 2011;44:813–6.

    Article  CAS  PubMed  Google Scholar 

  34. Xu X, Ling Q, Wang J, Xie H, Wei X, Lu D, et al. Donor miR-196a-2 polymorphism is associated with hepatocellular carcinoma recurrence after liver transplantation in a Han Chinese population. Int J Cancer. 2016;138:620–9.

    Article  CAS  PubMed  Google Scholar 

  35. Ng F, Wong K, Guan S, Mustafa F, Kajiji T, Bist P, et al. Annexin-1-deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen-specific antibody responses in a mouse model of asthma. Clin Exp Allergy. 2011;41:1793–803.

    Article  CAS  PubMed  Google Scholar 

  36. Chung YW, Oh HY, Kim JY, Kim JH, Kim IY. Allergen-induced proteolytic cleavage of annexin-1 and activation of cytosolic phospholipase A2 in the lungs of a mouse model of asthma. Proteomics. 2004;4:3328–34.

    Article  CAS  PubMed  Google Scholar 

  37. Kwon JH, Lee JH, Kim KS, Chung YW, Kim IY. Regulation of cytosolic phospholipase A2 phosphorylation by proteolytic cleavage of annexin A1 in activated mast cells. J Immunol. 2012;188:5665–73.

    Article  CAS  PubMed  Google Scholar 

  38. Bandeira-Melo C, Bonavita AGC, Diaz BL, E Silva PM, Carvalho VF, Jose PJ, et al. A novel effect for annexin 1-derived peptide ac2-26: reduction of allergic inflammation in the rat. J Pharmacol Exp Ther. 2005;313:1416–22.

    Article  CAS  PubMed  Google Scholar 

  39. Comer BS, Camoretti-Mercado B, Kogut PC, Halayko AJ, Solway J, Gerthoffer WT. MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2014;307:L727–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Larner-Svensson HM, Williams AE, Tsitsiou E, Perry MM, Jiang X, Chung KF, et al. Pharmacological studies of the mechanism and function of interleukin-1β-induced miRNA-146a expression in primary human airway smooth muscle. Respir Res. 2010;11:68.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Taganov KD, Boldin MP, Chang K-J, Baltimore D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 2006;103:12481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen C, Yang S, Chaugai S, Wang Y, Wang DW. Meta-analysis of hsa-mir-499 polymorphism (rs3746444) for cancer risk: evidence from 31 case-control studies. BMC Med Genom. 2014;15:126.

    Article  Google Scholar 

  43. Wakashin H, Hirose K, Iwamoto I, Nakajima H. Role of IL-23-Th17 cell axis in allergic airway inflammation. Int Arch Allergy Immunol. 2009;149:108–12.

    Article  CAS  PubMed  Google Scholar 

  44. Peng J, Yang XO, Chang SH, Yang J, Dong C. IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation. Cell Res. 2010;20:62–71.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Hoang Kim Tu Trinh and Duy Le Pham contributed equally to this work.

    Hoang Kim Tu Trinh and Duy Le Pham are co-first authors.

Authors and Affiliations

  1. Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea

    Hoang Kim Tu Trinh, Duy Le Pham, Hae-Sim Park & Seung-Hyun Kim

  2. Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, South Korea

    Duy Le Pham, Ri-Yeon Kim & Hae-Sim Park

  3. Clinical Trial Center, Ajou University Medical Center, Suwon, South Korea

    Su-Chin Kim & Seung-Hyun Kim

Authors
  1. Hoang Kim Tu Trinh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Duy Le Pham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Su-Chin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ri-Yeon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hae-Sim Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seung-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seung-Hyun Kim.

Ethics declarations

Funding

This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (Grant Number 2015R1C1A2A01053492) and the Korea Health Technology R&D Project through a Korea Health Industry Development Institute (KHIDI) grant funded by the Ministry of Health and Welfare, Republic of Korea (Grant Number HI16C0992).

Conflict of interest

Trinh HKT, Pham DL, Kim S-C, Kim R-Y, Park H-S and Kim S-H declare no conflict of interest in relation to the contents of this review.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trinh, H.K.T., Pham, D.L., Kim, SC. et al. Association of the miR-196a2, miR-146a, and miR-499 Polymorphisms with Asthma Phenotypes in a Korean Population. Mol Diagn Ther 21, 547–554 (2017). https://doi.org/10.1007/s40291-017-0280-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-017-0280-1

Keywords

Search

Navigation