Inflammation Research

, Volume 68, Issue 3, pp 215–221 | Cite as

miR-196a2 (rs11614913) polymorphism is associated with coronary artery disease, but not with in-stent coronary restenosis

  • José Manuel Fragoso
  • Julian Ramírez-Bello
  • Marco Antonio Martínez-Ríos
  • Marco Antonio Peña-Duque
  • Rosalinda Posadas-Sánchez
  • Hilda Delgadillo-Rodríguez
  • Mayra Jiménez-Morales
  • Carlos Posadas-Romero
  • Gilberto Vargas-AlarcónEmail author
Original Research Paper



The aim of the study was to evaluate the association of miRNA-146a G/C (rs2910164), and miRNA-196a2 C/T (rs11614913) polymorphisms with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent.

Materials and methods

The polymorphisms were determined in 218 patients with CAD who underwent coronary artery stenting (66 with restenosis and 152 without restenosis) and 611 healthy controls using 5′ exonuclease TaqMan assays.


The distribution of both polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under co-dominant, dominant and additive genetic models, the T allele of the miRNA-196a2 C/T (rs11614913) polymorphism was associated with increased risk of CAD (OR = 2.18, Pco–dom = 0.006, OR = 1.86, Pdom = 0.002, and OR = 1.52, Padd = 0.002, respectively). All models were adjusted for age, type 2 diabetes mellitus, dyslipidemia, hypertension and smoking habit. The “GT” haplotype was associated with increased risk of developing CAD (OR = 1.36, P = 0.046).


Our data suggests that the T allele of the miRNA-196a2 C/T (rs11614913) polymorphism is associated with the risk of developing CAD, but no association with restenosis was observed.


Coronary artery disease Coronary stenting MicroRNA Polymorphism Restenosis 



This work was supported in part by grants from the Consejo Nacional de Ciencia y Tecnología (Project number 233277), Mexico City, Mexico. The authors are grateful to the study participants. Institutional Review Board approval was obtained for all sample collections. The authors are grateful to Marva Ilian Arellano Gonzalez for her technical assistance.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.


  1. 1.
    Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, Smith K, Fournadjieva J, Suddath WO, Satler LF, Pichard AD, Kent KM, Waksman R. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation. 2006;113:1108–13.CrossRefGoogle Scholar
  2. 2.
    Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Kang SJ, Park SJ, Lee JH, Choi SW, Seong IW, Lee NH, Cho YH, Shin WY, Lee SJ, Lee SW, Hyon MS, Bang DW, Choi YJ, Kim HS, Lee BK, Lee K, Park HK, Park CB, Lee SG, Kim MK, Park KH, Park WJ, DECLARE-LONG II Study Investigators et al. A randomized, double-blind, multicenter comparison study of triple antiplatelet therapy with dual antiplatelet therapy to reduce restenosis after drug-eluting stent implantation in long coronary lesions results from the DECLARE-LONG II (drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with long coronary lesions) trial. J Am Coll Cardiol. 2011;57:1264–70.CrossRefGoogle Scholar
  3. 3.
    Hamasaki S, Tei C. Effect of coronary endothelial function on outcomes in patients undergoing percutaneous coronary intervention. J Cardiol. 2011;57:231–8.CrossRefGoogle Scholar
  4. 4.
    Latib A, Mussardo M, Ielasi A, Tarsia G, Godino C, Al-Lamee R, Chieffo A, Airoldi F, Carlino M, Montorfano M, Colombo A. Long-term outcomes after the percutaneous treatment of drug-eluting stent restenosis. JACC Cardiovasc Interv. 2011;4:155–64.CrossRefGoogle Scholar
  5. 5.
    Costa MA, Simon DI. Molecular basis of restenosis and drug-eluting stents. Circulation. 2005;111:2257–73.CrossRefGoogle Scholar
  6. 6.
    Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.CrossRefGoogle Scholar
  7. 7.
    Ren J, Zhang J, Xu N, Han G, Geng Q, Song J, Li S, Zhao J, Chen H. Signature of circulating MicroRNAs as potential biomarkers in vulnerable coronary artery disease. PLoS One. 2013;8:e80738.CrossRefGoogle Scholar
  8. 8.
    Qin S, Zhang C. microRNAs in vascular disease. J Cardiovasc Pharmacol. 2011;57:8–12.CrossRefGoogle Scholar
  9. 9.
    Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107:677–84.CrossRefGoogle Scholar
  10. 10.
    Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease. Circulation. 2010;121:1022–32.CrossRefGoogle Scholar
  11. 11.
    Corsten MF, Dennert R, Jochems S, Kuznetsova T, Devaux Y, Hofstra L, Wagner DR, Staessen JA, Heymans S, Schroen B. Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet. 2010;3:499–506.CrossRefGoogle Scholar
  12. 12.
    Gomes da Silva AM, Silbiger VN. miRNAs as biomarkers of atrial fibrillation. Biomarkers. 2014;19:631–6.CrossRefGoogle Scholar
  13. 13.
    Gareri C, De Rosa S, Indolfi C. MicroRNAs for restenosis and thrombosis after vascular injury. Circ Res. 2016;118:1170–84.CrossRefGoogle Scholar
  14. 14.
    Santulli G. MicroRNAs distinctively regulate vascular smooth muscle and endothelial cells: functional implications in angiogenesis, atherosclerosis, and in-stent restenosis. Adv Exp Med Biol. 2015;887:53–77.CrossRefGoogle Scholar
  15. 15.
    Wang D, Deuse T, Stubbendorff M, Chernogubova E, Erben RG, Eken SM, Jin H, Li Y, Busch A, Heeger CH, Behnisch B, Reichenspurner H, Robbins RC, Spin JM, Tsao PS, Schrepfer S, Maegdefessel L. Local MicroRNA modulation using a novel anti-miR-21-eluting stent effectively prevents experimental in-stent restenosis. Arterioscler Thromb Vasc Biol. 2015;35:1945–53.CrossRefGoogle Scholar
  16. 16.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefGoogle Scholar
  17. 17.
    He M, Gong Y, Shi J, Pan Z, Zou H, Sun D, Tu X, Tan X, Li J, Li W, Liu B, Xue J, Sheng L, Xiu C, Yang N, Xue H, Ding X, Yu C, Li Y. Plasma microRNAs as potential noninvasive biomarkers for in-stent restenosis. PLoS One. 2014;9:e112043.CrossRefGoogle Scholar
  18. 18.
    Liu H, Chen M, Wu F, Li F, Yin T, Cheng H, Li W, Liu B, Wang Q, Tao L. rs2910164 polymorphism confers a decreased risk for pulmonary hypertension by compromising the processing of microRNA-146a. Cell Physiol Biochem. 2015;36:1952–60.Google Scholar
  19. 19.
    Gu JY, Tu L. Investigating the role of polymorphisms in miR-146a, -149, and -196a2 in the development of gastric cancer. Genet Mol Res. 2016;15:027839.Google Scholar
  20. 20.
    Huang S, Lv Z, Deng Q, Li L, Yang B, Feng J, Wu T, Zhang X, Cheng J. A genetic variant in pre-miR-146a (rs2910164 C/G) is associated with the decreased risk of acute coronary syndrome in a Chinese population. Tohoku J Exp Med. 2015;237:227–33.CrossRefGoogle Scholar
  21. 21.
    Bao MH, Xiao Y, Zhang QS, Luo HQ, Luo J, Zhao J, Li GY, Zeng J, Li JM. Meta-analysis of miR-146a associated with coronary artery diseases and ischemic stroke. Int J Mol Sci. 2015;16:14305–17.CrossRefGoogle Scholar
  22. 22.
    Wang N, Li Y, Zhu LJ, Zhou RM, Jin W, Guo XQ, Wang CM, Chen ZF, Liu W. A functional polymorphism rs11614913 in microRNA-196a2 is associated with an increased risk of colorectal cancer although not with tumor stage and grade. Biomed Rep. 2013;1:737–42.CrossRefGoogle Scholar
  23. 23.
    Buraczynska M, Zukowski P, Wacinski P, Ksiazek K, Zaluska W. Polymorphism in microRNA-196a2 contributes to the risk of cardiovascular disease in type 2 diabetes patients. J Diabetes Complicat. 2014;28:617–20.CrossRefGoogle Scholar
  24. 24.
    Li T, Niu L, Wu L, Gao X, Li M, Liu W, Yang L, Liu D. A functional polymorphism in microRNA-196a2 is associated with increased susceptibility to non-Hodgkin lymphoma. Tumor Biol. 2015;36:3279–84.CrossRefGoogle Scholar
  25. 25.
    Ren YG, Zhuo XM, Cui ZG, Hou G. Effects of common polymorphisms in miR-146a and miR-196a2 on lung cancer susceptibility: a meta-analysis. J Thorac Dis. 2016;8:1297–305.CrossRefGoogle Scholar
  26. 26.
    Xiong XD, Cho M, Cai XP, Cheng J, Jing X, Cen JM, Liu X, Yang XL, Suh Y. A common variant in pre-miR-146 is associated with coronary artery disease risk and its mature miRNA expression. Mutat Res. 2014;761:15–20.CrossRefGoogle Scholar
  27. 27.
    Zhou K, Yue P, Ma F, Yan H, Zhang Y, Wang C, Qiu D, Hua Y, Li Y. Interpreting the various associations of MiRNA polymorphisms with susceptibilities of cardiovascular diseases: current evidence based on a systematic review and meta-analysis. Medicine (Baltimore). 2018;97:e10712.CrossRefGoogle Scholar
  28. 28.
    Wang Y, Wang X, Li Z, Chen L, Zhou L, Li C, Ouyang DS. Two single nucleotide polymorphisms (rs2431697 and rs2910164) of miR-146a are associated with risk of coronary artery disease. Int J Environ Res Public Health. 2017;14:E514.CrossRefGoogle Scholar
  29. 29.
    Bastami M, Ghaderian SM, Omrani MD, Mirfakhraie R, Vakili H, Parsa SA, Nariman-Saleh-Fam Z, Masotti A. MiRNA-related polymorphisms in miR-146a and TCF21 are associated with increased susceptibility to coronary artery disease in an Iranian population. Genet Test Mol Biomark. 2016;20:241–8.CrossRefGoogle Scholar
  30. 30.
    Zhou HY, Wei Q, Shi XD, Cao HY, Qin L. miR-146a rs2910164 polymorphism might be associated with coronary artery disease risk in Asians. Cell Mol Biol (Noisy-le-grand). 2017;63:27–9.CrossRefGoogle Scholar
  31. 31.
    Sung JH, Kim SH, Yang WI, Kim WJ, Moon JY, Kim IJ, Cha DH, Cho SY, Kim JO, Kim KA, Kim OJ, Lim SW, Kim NK. miRNA polymorphisms (miR146a, miR149, miR196a2 and miR499) are associated with the risk of coronary artery disease. Mol Med Rep. 2016;14:2328–42.CrossRefGoogle Scholar
  32. 32.
    Zhi H, Wang L, Ma G, Ye X, Yu X, Zhu Y, Zhang Y, Zhang J, Wang B. Polymorphisms of miRNAs genes are associated with the risk and prognosis of coronary artery disease. Clin Res Cardiol. 2012;101:289–96.CrossRefGoogle Scholar
  33. 33.
    Lahiri DK, Nurnberger JrJI. A rapid non-enzymatic method for the preparation HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19:5444.CrossRefGoogle Scholar
  34. 34.
    Yuan HY, Chiou JJ, Tseng WH, Liu CH, Liu CK, Lin YJ, Wang HH, Yao A, Chen YT, Hsu CN. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res. 2006;34(web server issue):W635–41.CrossRefGoogle Scholar
  35. 35.
    Xu Z, Taylor JA. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res. 2009;37(Web Server Issue):W600–05.CrossRefGoogle Scholar
  36. 36.
    Zhou B, Rao L, Peng Y, Wang Y, Chen Y, Song Y, Zhang L. Common genetic polymorphisms in pre-microRNAs were associated with increased risk of dilated cardiomyopathy. Clin Chim Acta. 2010;411:1287–90.CrossRefGoogle Scholar
  37. 37.
    Xu J, Hu Z, Xu ZF, Gu H, Yi L, Cao H, Chen J, Tian T, Liang J, Lin Y, Qiu W, Ma H, Shen H, Chen Y. Functional variant in microRNA-196a2 contributes to the susceptibility of congenital heart disease in a Chinese population. Hum Mutat. 2009;30:1231–6.CrossRefGoogle Scholar
  38. 38.
    Sun R, Liu M, Lu L, Zheng Y, Zhang P. Congenital heart disease: causes, diagnosis, symptoms, and treatments. Cell Biochem Biophys. 2015;72:857–60.CrossRefGoogle Scholar
  39. 39.
    Watkins H, Farrall M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat Rev Genet. 2006;7:163–73.CrossRefGoogle Scholar
  40. 40.
    Toraih EA, Ismail NM, Toraih AA, Hussein MH4, 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.CrossRefGoogle Scholar
  41. 41.
    Fragoso Lona JM, Sierra Martínez M, Vargas Alarcón G, Barrios Rodas A, Ramírez Bello J. Tumor necrosis factor alfa in cardiovascular diseases: molecular biology and genetics. Gac Med Mex. 2013;149:521–30.Google Scholar
  42. 42.
    Luthra R, Singh RR, Luthra MG, Li YX, Hannah C, Romans AM, Barkoh BA, Chen SS, Ensor J, Maru DM, Broaddus RR, Rashid A, Albarracin CT. MicroRNA-196a2 targets annexin A1: a microRNA mediated mechanism of annexin A1 downregulation in cancers. Oncogene. 2008;27:6667–78.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • José Manuel Fragoso
    • 1
  • Julian Ramírez-Bello
    • 2
  • Marco Antonio Martínez-Ríos
    • 3
  • Marco Antonio Peña-Duque
    • 3
  • Rosalinda Posadas-Sánchez
    • 4
  • Hilda Delgadillo-Rodríguez
    • 3
  • Mayra Jiménez-Morales
    • 2
  • Carlos Posadas-Romero
    • 4
  • Gilberto Vargas-Alarcón
    • 1
    Email author
  1. 1.Department of Molecular BiologyInstituto Nacional de Cardiología Ignacio ChávezMexico CityMexico
  2. 2.Endocrine and Metabolic Diseases Research UnitHospital Juárez de MexicoMexico CityMexico
  3. 3.Interventional CardiologyInstituto Nacional de Cardiología Ignacio ChávezMexico CityMexico
  4. 4.Department of EndocrinologyInstituto Nacional de Cardiología Ignacio ChávezMexico CityMexico

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