Association of MicroRNA146a G>C and MicroRNA196a-2 C>T Gene Polymorphisms with Outcome of Kidney Transplantation in Iranian Patients
,
Abstract
Acute organ rejection remains a serious clinical challenge. Novel accessible biomarkers of acute rejection could easily enable us to detect the rejection earlier and make more fine-tuned calibration of immunosuppressive or new target treatment possible. Control of gene expression by microRNAs influences many cellular functions, including cellular differentiation, cell proliferation, cell development, and functional regulation of the immune system. Therefore, this study was aimed to investigate if miRNA146a G>C and miRNA196a-2 C>T gene polymorphisms are associated with kidney transplant rejection in Iranian patients. Tissue samples were collected from 100 renal transplant patients between the years 2009 and 2013. The miRNA146a G>C (rs2910164) and miRNA196a-2 C>T (rs11614913) gene polymorphisms were evaluated in kidney transplant patients; using the in-house-polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In this study, we found that the CC genotype, C and G alleles of the miRNA146a G>C polymorphism was associated with increased risk of transplant rejection in kidney transplant patients (p=0.003, p=0.01 and p=0.01), respectively. The CC genotype, T, and C alleles of the miRNA196a-2 C>T were also significantly more frequent in transplanted patients compared to healthy controls (p=0.02, p=0.05, and p=0.05), respectively. However, significant associations were not found between miRNA196a-2 C>T polymorphisms and kidney transplant rejection. The CC genotype, G, and C allele of the miRNA146a G>C and also, the CC genotype, T and C alleles of the miRNA196a-2 C>T may be genetically susceptible factors for transplant rejection and development of kidney disorders, especially in Iranian patients. Further studies are required to validate these findings in a larger population, as well as in patients with different ethnic origins.
1. Misra MK, Pandey SK, Kapoor R, Sharma RK, Agrawal S. Genetic variants of MicroRNA-related genes in susceptibility and prognosis of end-stage renal disease and renal allograft outcome among north Indians. Pharmacogenet Genomics. 2014;24(9):442-50.
2. Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States renal data system. Clin J Am Soc Nephrol. 2007;18(10):2644-8.
3. Anglicheau D, Sharma VK, Ding R, Hummel A, Snopkowski C, Dadhania D, et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A. 2009;106(13):5330-5.
4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism and function. Cell. 2004;116(2):281-97.
5. Yoshizawa S, Umezo T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, et al. Exosomal miRNA signatures for late-onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Int J Mol Sci. 2018;19(9):2493.
6. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597-610.
7. Khalid U, Newbury L, Simpson K, Jenkins RH, Bowen T, Bates L, et al. A urinary microRNA panel that is an early predictive biomarker of delayed graft function following kidney transplantation. Sci Rep. 2019;9(1):3584.
8. Sarma NJ, Tiriveedhi V, Ramachandran S, Crippin J, Chapman W, Mohanakumar T. Modulation of immune responses following solid organ transplantation by microRNA. Exp Mol Pathol. 2012;93(3):378-85.
9. Khalid U, Bowen T, Fraser DJ, Jenkins RH. Acute kidney injury: a paradigm for miRNA regulation of the cell cycle. Biochem Soc Trans. 2014;42(4):1219-23.
10. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012;13(5):358-69.
11. Jafari Ghods F. Trends of non-coding RNAs research in acute rejection after kidney transplantation. Non-coding RNA Investigation. 2019;3:16.
12. Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, Lacomini J. Identification of a microRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci U S A. 2010;107(32):14339-44.
13. Naesens M, Khatri P, Li L, Sigdel TK, Vitalone MJ, Chen R, et al. Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes. Kidney Int. 2011;80(12):1364-76.
14. Salvadori M, Tsalouchos A. Biomarkers in renal transplantation: an updated review. World J Transplant. 2017;7(3):161-178.
15. Mas VR, Mueller TF, Archer KJ, Maluf DG. Identifying biomarkers as diagnostic tools in kidney transplantation. Expert Rev Mol Diagn. 2011;11(2):183-96.
16. Naesens M, Sarwal MM. Molecular diagnostics in transplantation. Nat Rev Nephrol. 2010;6(10):614-28.
17. Iravani-Saadi M, Yaghobi R, Karimi MH, Geramizadeh B, Ramzi M, Zakerinia M. Association of the costimulatory molecule gene polymprphisms and active cytomegalovirus infection in hematopoietic stem cell transplant patients. Mol Biol Rep. 2013;40(10):5833-42.
18. Iravani-Saadi M, Karimi MH, Yaghobi R, Geramizadeh B, Ramzi M, Niknam A, et al. Polymorphism of costimulatory molecules (CTLA4, ICOS, PD.1 and CD28) and allogeneic hematopoietic stem cell transplantation in Iranian patients. Immunol Invest. 2014;43(4):391-404.
19. Karimi MH, Motazedian M, Abedi F, Yaghobi R, Geramizadeh B, Nikeghbalian S. Association of genetic variation in co-stimulatory molecule genes with outcome of liver transplant in Iranian patients. Gene. 2012;504(1):127-32.
20. Loktionov A. Common gene polymorphisms, cancer progression and prognosis. Cancer Lett. 2004;208(1):1-33.
21. Lin J, Huang Y, Zhang X, Chen J, Sheng H. Association of miR-146a rs2910164 with childhood IgA nephropathy. Pediatr Nephrol. 2014;29(10):1979-86.
22. O'neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol. 2011;11(3):163-75.
23. Yang B, Wei W, Shi Y, Huang Z, Cai B, Zhang J, et al. Genetic variation in miR-146a is not associated with susceptibility to IgA nephropathy in adults from a Chinese Han population. PloS One. 2015;10(10):e0139554.
24. Zhang H, Su YL, Yu H, Qian BY. Meta-analysis of the association between mir-196a-2 polymorphism and cancer susceptibility. Cancer Biol Med. 2012;9(1):63-72.
25. Hu Z, et al. Genetic variants of miRNA sequences and non–small cell lung cancer survival. J Clin Invest. 2008;118(7):2600-8.
26. 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(3):620-9.
27. Li XD, Li ZG, Song XX, Liu CF. A variant in microRNA196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology. 2010;42(7):669-73.
28. Zhang C, Liang S, Cheng S, Li W, Wang X, Zheng C, et al. Urinary miR-196a predicts disease progression in patients with chronic kidney disease. J Transl Med. 2018;16(1):91.
29. Xu Y, Liu L, Liu J, Zhang Y, Zhu J, Chen J, et al. A potentially functional polymorphism in the promoter region of miR-34b/c is associated with an increased risk for primary hepatocellular carcinoma. Int J Cancer. 2011;128(2):412-7.
30. 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(14):5970-7.
31. Huang F, Tang J, Zhuang X, Zhuang Y, Cheng W, Chen W, et al. MiR-196a promotes pancreatic cancer progression by targeting nuclear factor kappa-B-inhibitor alpha. PloS One. 2014;9(2):e87897.
32. Han Q, Zhou C, Liu F, Xu G, Zheng R, Zhang X. MicroRNA-196a post-transcriptionally upregulates the UBE2C proto-oncogene and promotes cell proliferation in breast cancer. Oncol Rep. 2015;34(2):877-83.
33. Chen ZY, Chen X, Wang ZX. The role of microRNA-196a in tumorigenesis, tumor progression, and prognosis. Tumour Biol. 2016;37(12):15457-66.
34. Shao Y, Li J, Cai Y, Xie Y, Ma G, Li Y, et al. The functional polymorphisms of miR-146a are associated with susceptibility to severe sepsis in the Chinese population. Mediators Inflamm. 2014;916202.
35. Löfgren SE, et al. Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun. 2012;13(3):268-74.
36. Kadkhodazadeh M, Jafari AR, Amid R, Ebadian AR, Alipour MM, Mollaverdi F, et al. MiR146a and MiR499 gene polymorphisms in Iranian periodontitis and peri-implantitis patients. J Long Term Eff Med Implants. 2013;23(1):9-16.
37. Chen ZF, Ma LL, Xue HB. Common polymorphisms of the microRNA genes (miR-146a and miR-196a-2) and gastric cancer risk: an updated meta-analysis. Genet Mol Res. 2015;14(3):8589-601.
38. Cui Y, She K, Tian D, Zhang P, Xin X. MiR-146a inhibits proliferation and enhances chemosensitivity in epithelial ovarian cancer via reduction of SOD2. Oncol Res. 2016;23(6):275-82.
39. Sasaki H, Yoshiike M, Nozawa S, Usuba W, Katsuoka Y, Aida K, et al. Expression level of urinary microRNA-146a-5p is increased in patients with bladder cancer and decreased in those after transurethral resection. Clin Genitourin Cancer. 2016;14(5):e493-e499.
40. Deng S, Wang W, Li X, Zhang P. Common genetic polymorphisms in pre-microRNAs and risk of bladder cancer. World J Surg Oncol. 2015; 13(13):297.
41. Yang H, Lu QL, Wu XJ, Ma HY, Qu YY, Zhang DZ, et al. Association of genetic variations in miR-146a rs2910164 and miR-149 rs11614913 with the development of classic Kaposi sarcoma. Genet Mol Res. 2016;15(4).
42. Stickel N, Hanke K, Marschner D, Prinz G, Köhler M, Melchinger W, et al. MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia. 2017; 31(12):2732-2741.
43. Srivastava K, Tyagi K. Single nucleotide polymorphisms of microRNA in cardiovascular diseases. Clin Chim Acta. 2018;478:101-110.
44. Du M, Lu D, Wang Q, Chu H, Tong N, Pan X, et al. Genetic variations in microRNAs and the risk and survival of renal cell cancer. Carcinogenesis. 2014;35(7): 1629-35.
45. Ji JD, Cha ES, Lee WJ. Association of miR-146-a polymorphisms with systemic lupus erythematosus: a meta-analysis. Lupus. 2014;23(10):1023-30.
46. Zhang W, et al. A Single nucleotide polymorphism of miR-146a and psoriasis: an association and functional study. J Cell Mol Med. 2014:18(11):2225-34.
2. Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States renal data system. Clin J Am Soc Nephrol. 2007;18(10):2644-8.
3. Anglicheau D, Sharma VK, Ding R, Hummel A, Snopkowski C, Dadhania D, et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A. 2009;106(13):5330-5.
4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism and function. Cell. 2004;116(2):281-97.
5. Yoshizawa S, Umezo T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, et al. Exosomal miRNA signatures for late-onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Int J Mol Sci. 2018;19(9):2493.
6. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597-610.
7. Khalid U, Newbury L, Simpson K, Jenkins RH, Bowen T, Bates L, et al. A urinary microRNA panel that is an early predictive biomarker of delayed graft function following kidney transplantation. Sci Rep. 2019;9(1):3584.
8. Sarma NJ, Tiriveedhi V, Ramachandran S, Crippin J, Chapman W, Mohanakumar T. Modulation of immune responses following solid organ transplantation by microRNA. Exp Mol Pathol. 2012;93(3):378-85.
9. Khalid U, Bowen T, Fraser DJ, Jenkins RH. Acute kidney injury: a paradigm for miRNA regulation of the cell cycle. Biochem Soc Trans. 2014;42(4):1219-23.
10. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012;13(5):358-69.
11. Jafari Ghods F. Trends of non-coding RNAs research in acute rejection after kidney transplantation. Non-coding RNA Investigation. 2019;3:16.
12. Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, Lacomini J. Identification of a microRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci U S A. 2010;107(32):14339-44.
13. Naesens M, Khatri P, Li L, Sigdel TK, Vitalone MJ, Chen R, et al. Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes. Kidney Int. 2011;80(12):1364-76.
14. Salvadori M, Tsalouchos A. Biomarkers in renal transplantation: an updated review. World J Transplant. 2017;7(3):161-178.
15. Mas VR, Mueller TF, Archer KJ, Maluf DG. Identifying biomarkers as diagnostic tools in kidney transplantation. Expert Rev Mol Diagn. 2011;11(2):183-96.
16. Naesens M, Sarwal MM. Molecular diagnostics in transplantation. Nat Rev Nephrol. 2010;6(10):614-28.
17. Iravani-Saadi M, Yaghobi R, Karimi MH, Geramizadeh B, Ramzi M, Zakerinia M. Association of the costimulatory molecule gene polymprphisms and active cytomegalovirus infection in hematopoietic stem cell transplant patients. Mol Biol Rep. 2013;40(10):5833-42.
18. Iravani-Saadi M, Karimi MH, Yaghobi R, Geramizadeh B, Ramzi M, Niknam A, et al. Polymorphism of costimulatory molecules (CTLA4, ICOS, PD.1 and CD28) and allogeneic hematopoietic stem cell transplantation in Iranian patients. Immunol Invest. 2014;43(4):391-404.
19. Karimi MH, Motazedian M, Abedi F, Yaghobi R, Geramizadeh B, Nikeghbalian S. Association of genetic variation in co-stimulatory molecule genes with outcome of liver transplant in Iranian patients. Gene. 2012;504(1):127-32.
20. Loktionov A. Common gene polymorphisms, cancer progression and prognosis. Cancer Lett. 2004;208(1):1-33.
21. Lin J, Huang Y, Zhang X, Chen J, Sheng H. Association of miR-146a rs2910164 with childhood IgA nephropathy. Pediatr Nephrol. 2014;29(10):1979-86.
22. O'neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol. 2011;11(3):163-75.
23. Yang B, Wei W, Shi Y, Huang Z, Cai B, Zhang J, et al. Genetic variation in miR-146a is not associated with susceptibility to IgA nephropathy in adults from a Chinese Han population. PloS One. 2015;10(10):e0139554.
24. Zhang H, Su YL, Yu H, Qian BY. Meta-analysis of the association between mir-196a-2 polymorphism and cancer susceptibility. Cancer Biol Med. 2012;9(1):63-72.
25. Hu Z, et al. Genetic variants of miRNA sequences and non–small cell lung cancer survival. J Clin Invest. 2008;118(7):2600-8.
26. 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(3):620-9.
27. Li XD, Li ZG, Song XX, Liu CF. A variant in microRNA196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology. 2010;42(7):669-73.
28. Zhang C, Liang S, Cheng S, Li W, Wang X, Zheng C, et al. Urinary miR-196a predicts disease progression in patients with chronic kidney disease. J Transl Med. 2018;16(1):91.
29. Xu Y, Liu L, Liu J, Zhang Y, Zhu J, Chen J, et al. A potentially functional polymorphism in the promoter region of miR-34b/c is associated with an increased risk for primary hepatocellular carcinoma. Int J Cancer. 2011;128(2):412-7.
30. 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(14):5970-7.
31. Huang F, Tang J, Zhuang X, Zhuang Y, Cheng W, Chen W, et al. MiR-196a promotes pancreatic cancer progression by targeting nuclear factor kappa-B-inhibitor alpha. PloS One. 2014;9(2):e87897.
32. Han Q, Zhou C, Liu F, Xu G, Zheng R, Zhang X. MicroRNA-196a post-transcriptionally upregulates the UBE2C proto-oncogene and promotes cell proliferation in breast cancer. Oncol Rep. 2015;34(2):877-83.
33. Chen ZY, Chen X, Wang ZX. The role of microRNA-196a in tumorigenesis, tumor progression, and prognosis. Tumour Biol. 2016;37(12):15457-66.
34. Shao Y, Li J, Cai Y, Xie Y, Ma G, Li Y, et al. The functional polymorphisms of miR-146a are associated with susceptibility to severe sepsis in the Chinese population. Mediators Inflamm. 2014;916202.
35. Löfgren SE, et al. Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun. 2012;13(3):268-74.
36. Kadkhodazadeh M, Jafari AR, Amid R, Ebadian AR, Alipour MM, Mollaverdi F, et al. MiR146a and MiR499 gene polymorphisms in Iranian periodontitis and peri-implantitis patients. J Long Term Eff Med Implants. 2013;23(1):9-16.
37. Chen ZF, Ma LL, Xue HB. Common polymorphisms of the microRNA genes (miR-146a and miR-196a-2) and gastric cancer risk: an updated meta-analysis. Genet Mol Res. 2015;14(3):8589-601.
38. Cui Y, She K, Tian D, Zhang P, Xin X. MiR-146a inhibits proliferation and enhances chemosensitivity in epithelial ovarian cancer via reduction of SOD2. Oncol Res. 2016;23(6):275-82.
39. Sasaki H, Yoshiike M, Nozawa S, Usuba W, Katsuoka Y, Aida K, et al. Expression level of urinary microRNA-146a-5p is increased in patients with bladder cancer and decreased in those after transurethral resection. Clin Genitourin Cancer. 2016;14(5):e493-e499.
40. Deng S, Wang W, Li X, Zhang P. Common genetic polymorphisms in pre-microRNAs and risk of bladder cancer. World J Surg Oncol. 2015; 13(13):297.
41. Yang H, Lu QL, Wu XJ, Ma HY, Qu YY, Zhang DZ, et al. Association of genetic variations in miR-146a rs2910164 and miR-149 rs11614913 with the development of classic Kaposi sarcoma. Genet Mol Res. 2016;15(4).
42. Stickel N, Hanke K, Marschner D, Prinz G, Köhler M, Melchinger W, et al. MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia. 2017; 31(12):2732-2741.
43. Srivastava K, Tyagi K. Single nucleotide polymorphisms of microRNA in cardiovascular diseases. Clin Chim Acta. 2018;478:101-110.
44. Du M, Lu D, Wang Q, Chu H, Tong N, Pan X, et al. Genetic variations in microRNAs and the risk and survival of renal cell cancer. Carcinogenesis. 2014;35(7): 1629-35.
45. Ji JD, Cha ES, Lee WJ. Association of miR-146-a polymorphisms with systemic lupus erythematosus: a meta-analysis. Lupus. 2014;23(10):1023-30.
46. Zhang W, et al. A Single nucleotide polymorphism of miR-146a and psoriasis: an association and functional study. J Cell Mol Med. 2014:18(11):2225-34.
| Files | ||
| Issue | Vol 19 No 6 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v19i6.4931 | |
| PMID | 33463131 | |
| Keywords | ||
| Kidney transplantation MicroRNAs Polymorphism | ||
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How to Cite
1.
Abbasi A, Ebadi P, Yaghobi R, Karimi MH. Association of MicroRNA146a G>C and MicroRNA196a-2 C>T Gene Polymorphisms with Outcome of Kidney Transplantation in Iranian Patients. Iran J Allergy Asthma Immunol. 2020;19(6):624-631.
