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miR-146a Polymorphism Influences Levels of miR-146a, IRAK-1, and TRAF-6 in Young Patients with Coronary Artery Disease

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Abstract

Modulation of nuclear factor KappaB (NF-κB) activation may play a role in regulating inflammatory conditions associated with coronary artery disease (CAD). MicroRNA-146a (miR-146a) primarily targets interleukin-1 receptor-associated kinase 1 (IRAK-1) and tumour necrosis factor receptor associated factor 6 (TRAF-6), which results in inhibition of NF-κB via the TLR pathway. This study investigated the influence of the miR-146a GC rs2910164 on miR-146a expression in young South African Indians with CAD. CAD patients and controls were genotyped by PCR–RFLP and miRNA-146a levels were measured by qPCR. IRAK-1, TRAF-6 and NF-κB expression was determined by Western blot. No differences in genotypic frequency was found (GG: 45 vs. 47 %, GC: 46 vs. 41 %, CC: 9 vs. 12 %) in controls and patients respectively (odds ratio = 1.025; 95 % confidence interval 0.6782–1.550; p = 0.9164). Significantly higher levels of miR-146a was associated with CAD patients with the CC genotype (6.25-fold increase relative to controls and patients with the wildtype variant, p < 0.0001). Significantly lower levels of IRAK-1 (0.38 ± 0.02; p = 0.0072) and TRAF-6 (0.44 ± 0.02; p = 0.0146) was found in CAD patients with the CC genotype. The lowest levels of NF-κB and C-reactive protein were found in patients with the homozygous C allele compared to the heterozygous GC and wildtype variants. We propose a role for miR-146a in TLR signalling through a negative feedback mechanism involving the attenuation of NF-κB by down-regulation of IRAK-1 and TRAF-6. Our observations implicate miR-146a as a target for lowering inflammation in CAD patients.

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References

  1. Hung, P. S., Chang, K. W., Kao, S. Y., Chu, T. H., Liu, C. J., & Lin, S. C. (2012). Association between the rs2910164 polymorphism in pre-mir-146a and oral carcinoma progression. Oral Oncology, 48, 404–408.

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi, Y., Satoh, M., Minami, Y., Tabuchi, T., Itoh, T., & Nakamura, M. (2010). Expression of miR-146a/b is associated with the Toll-like receptor 4 signal in coronary artery disease: Effect of renin-angiotensin system blockade and statins on miRNA-146a/b and Toll-like receptor 4 levels. Clinical Science, 119, 395–405.

    Article  CAS  PubMed  Google Scholar 

  3. Zorc, M., Jevsinek Skok, D., Godnic, I., Calin, G. A., Horvat, S., Jiang, Z., et al. (2012). Catalog of microRNA seed polymorphisms in vertebrates. PLoS ONE, 7(1), e30737.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Ellwanger, D. C., Buttner, F. A., Mewes, H. W., & Stumpflen, V. (2011). The sufficient minimal set of miRNA seed types. Bioinformatics, 27(10), 1346–1350.

    Article  CAS  PubMed  Google Scholar 

  5. Hu, Z., Liang, J., Wang, Z., Tian, T., Zhou, X., Chen, J., et al. (2008). Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Human Mutation, 30(1), 79–84.

    Article  Google Scholar 

  6. Mittal, R. D., Gangwar, R., George, G. P., Mittal, T., & Kapoor, R. (2011). Investigative role of pre-microRNAs in bladder cancer patients: A case-control study in North India. DNA and Cell Biology, 30(6), 401–406.

    Article  CAS  PubMed  Google Scholar 

  7. Li, L., Chen, X., & Li, Y. (2010). MicroRNA-146a and human disease. Scandinavian Journal of Immunology, 71, 227–231.

    Article  CAS  PubMed  Google Scholar 

  8. Yang, B., Chen, J., Li, Y., Zhang, J., Li, D., Huang, Z., et al. (2012). Association of polymorphisms in pre-miRNA with inflammatory biomarkers in rheumatoid arthritis in the Chinese Han population. Human Immunology, 73, 101–106.

    Article  CAS  PubMed  Google Scholar 

  9. Xu, T., Zhu, Y., Wei, Q., Yuan, Y., Zhou, F., Ge, Y., et al. (2008). A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis, 29(11), 2126–2131.

    Article  CAS  PubMed  Google Scholar 

  10. Li, D., Wang, T., Song, X., Qucuo, M., Yang, B., Zhang, J., et al. (2011). Genetic study of two single nucleotide polymorphisms within corresponding microRNAs and susceptibility to tuberculosis in a Chinese Tibetan and Han population. Human Immunology, 72, 598–602.

    Article  CAS  PubMed  Google Scholar 

  11. Raitoharju, E., Lyytikainen, L. P., Levula, M., Oksala, N., Mennander, A., Tarkka, M., et al. (2011). miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis, 219, 211–217.

    Article  CAS  PubMed  Google Scholar 

  12. Xu, J., Zhao, J., Evan, G., Xiao, C., Cheng, Y., & Xiao, J. (2012). Circulating microRNAs: Novel biomarkers for cardiovascular diseases. Journal of Molecular Medicine, 90, 865–875.

    Article  CAS  PubMed  Google Scholar 

  13. Jamaluddin, M. S., Weakly, S. M., Zhang, L., Kougias, P., Lin, P. H., Yao, Q., et al. (2011). miRNAs: Roles and clinical applications in vascular disease. Expert Review of Molecular Diagnostics, 11(1), 79–89.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Zilahi, E., Tarr, T., Papp, G., Griger, Z., Sipka, S., & Zeher, M. (2011). Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren’s syndrome. Immunology Letters, 141, 165–168.

    Article  PubMed  Google Scholar 

  15. Jazdzewski, K., Liyanarachchi, S., Swierniak, M., Pachucki, J., Ringel, M. D., Jarzab, B., et al. (2009). Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proceedings of the National Academy of Sciences, 106(5), 1502–1505.

    Article  CAS  Google Scholar 

  16. Chatzikyriakidou, A., Voulgari, P. V., Georgiou, I., & Drosos, A. A. (2010). A polymorphism in the 3′-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility. Joint Bone Spine, 77(5), 411–413.

    Article  CAS  PubMed  Google Scholar 

  17. Yue, C., Wang, M., Ding, B., Wang, W., Fu, S., Zhou, D., et al. (2011). Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population. Gynecologic Oncology, 122, 33–37.

    Article  CAS  PubMed  Google Scholar 

  18. Curtale, G., Citarella, F., Carissimi, C., Goldoni, M., Carucci, N., Fulci, V., et al. (2010). An emerging player in the adaptive immune response: MicroRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood, 115(2), 265–273.

    Article  CAS  PubMed  Google Scholar 

  19. Taganov, K. D., Boldin, M. P., Chang, K. J., & Baltimore, D. (2006). NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proceedings of the National Academy of Sciences, 103(33), 12481–12486.

    Article  CAS  Google Scholar 

  20. Mohan, V., Venkatraman, J. V., & Pradeepa, R. (2010). Epidemiology of cardiovascular disease in type 2 diabetes: The Indian scenario. Journal of Diabetes Science and Technology, 4(1), 158–170.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Murray, C. J., & Lopez, A. D. (1997). Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease study. The Lancet, 349, 1498–1504.

    Article  CAS  Google Scholar 

  22. Reddy, K. S., & Yusuf, S. (1998). Emerging epidemic of cardiovascular disease in developing countries. Circulation, 97(6), 596–601.

    Article  CAS  PubMed  Google Scholar 

  23. Seedat, Y. K. (2005). Review: Diabetes mellitus in South African Indians. The British Journal of Diabetes & Vascular Disease, 5(5), 249–251.

    Article  Google Scholar 

  24. Sharma, M., & Ganguly, N. (2005). Premature coronary artery disease in Indians and its associated risk factors. Vascular Health and Risk Management, 1(3), 217–225.

    PubMed Central  PubMed  Google Scholar 

  25. Norman, R., Bradshaw, D., Schneider, M., Pieterse, D., & Groenwald, P. (2006). Revised burden of disease estimates for the comparative risk factor assessment, South Africa 2000. Cape Town: Medical Research Council.

    Google Scholar 

  26. Sambrook, J., & Russell, D. W. (2001). Rapid isolation of mammalian DNA in molecular cloning: A laboratory manual (3rd ed.). New York: Cold Spring Harbor Laboratory Press.

    Google Scholar 

  27. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods, 25(4), 402–408.

    Article  CAS  PubMed  Google Scholar 

  28. Takeda, K., & Akira, S. (2004). TLR signalling pathways. Seminars in Immunology, 16, 3–9.

    Article  CAS  PubMed  Google Scholar 

  29. Pauley, K. M., Satoh, M., Chan, A. L., Bubb, M. R., Reeves, W. H., & Chan, E. K. (2008). Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Research & Therapy, 10(4), 101.

    Article  Google Scholar 

  30. Hirschfield, G. M., & Pepys, M. B. (2003). C-reactive protein and cardiovascular disease: New insights from an old molecule. QJM, 96(11), 793–807.

    Article  CAS  PubMed  Google Scholar 

  31. Shen, J., Ambrosone, C. B., DiCioccio, R., Odunsi, K., Lele, S. B., & Zhao, H. (2008). A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis. Carcinogenesis, 29(10), 1963–1966.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Research Foundation and College of Health Science Scholarships.

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None declared.

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Authors and Affiliations

  1. Discipline of Medical Biochemistry, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

    Prithiksha Ramkaran, Alisa Phulukdaree, Devapregasan Moodley & Anil A. Chuturgoon

  2. Department of Cardiology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

    Sajidah Khan

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  1. Prithiksha Ramkaran
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  2. Sajidah Khan
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Correspondence to Anil A. Chuturgoon.

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Ramkaran, P., Khan, S., Phulukdaree, A. et al. miR-146a Polymorphism Influences Levels of miR-146a, IRAK-1, and TRAF-6 in Young Patients with Coronary Artery Disease. Cell Biochem Biophys 68, 259–266 (2014). https://doi.org/10.1007/s12013-013-9704-7

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  • DOI: https://doi.org/10.1007/s12013-013-9704-7

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