Association Analysis of Single Nucleotide Polymorphisms in miR-146a and miR-196a2 on the Prevalence of Cancer in Elderly Japanese: A Case-Control Study

  • Parlayan, Cuneyd (Department of Molecular Epidemiology, Medical Research Institute) ;
  • Ikeda, Shinobu (Department of Molecular Epidemiology, Medical Research Institute) ;
  • Sato, Noriko (Department of Molecular Epidemiology, Medical Research Institute) ;
  • Sawabe, Motoji (Department of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University) ;
  • Muramatsu, Masaaki (Department of Molecular Epidemiology, Medical Research Institute) ;
  • Arai, Tomio (Department of Pathology, Tokyo Metropolitan Geriatric Hospital)
  • Published : 2014.03.01


Background: Single nucleotide polymorphisms (SNPs) affecting microRNA (miR) sequences may influence carcinogenesis. Our current study primarily aimed to confirm previously conducted association studies between rs2910164 found on miR-146a, and rs11614913 located on miR-196a2 polymorphisms and cancer phenotypes in the Japanese elderly population. rs2910164 (G/C) and rs11614913 (T/C) polymorphisms were determined by genotyping on the samples collected from 1,351 consecutive autopsy cases registered in the Japanese SNPs for geriatric research (JG-SNP) data base. Cancer samples were systematically reviewed, pathologically verified and assessed with respect to miR-146a and miR-196a2 genotypic variation. The current study covered 726 males and 625 females with a mean age of $80.3{\pm}8.9$ years. The study included 524 subjects without cancer and 827 subjects with at least one type of cancer, such as gastric (n=160), lung (n=148), colorectal (n=116) or others. Males with cancers (n=467) were more numerous than females (n=360). Both rs11614913 (CT: TT adjusted odds ratio (OR) 95% confidence interval (95%CI)=0.98 (0.75-1.28), p=0.873, CC: TT adjusted OR (95%CI)=1.06 (0.76-1.47), p=0.737, CT+CC: TT, adjusted OR (95%CI)=0.99 (0.77-1.29), p=0.990), and rs2910164 (CG: CC adjusted OR (95%CI)=1.12 (0.87-1.44), p=0.383, GG: CC adjusted OR (95%CI)=1.03 (0.71-1.48), p=0.887, CG+GG: CC adjusted OR (95%CI)=1.10 (0.87-1.39), p=0.446) polymorphisms did not show significant association with overall cancer in all subjects. However, "CC" genotype in rs11614913 polymorphism was significantly associated with increased gastric cancer (n=160) in all subjects (CC: CT+TT, adjusted OR (95%CI)=1.50 (1.02-2.22), p=0.040). We found that rs11614913 and rs2910164 do not pose general cancer risk, but rs11614913 may influence gastric cancer in Japanese elderly population. Confirmation of our study results requires further investigations with larger subject populations.


  1. Ambros V (2004). The functions of animal microRNAs. Nature, 431, 350-5.
  2. Bartel DP (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116, 281-97.
  3. Brennecke J, Hipfner DR, Stark A, et al (2003). bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell, 113, 25-36.
  4. Calvo R, West J, Franklin W, et al (2000). Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci USA, 97, 12776-81.
  5. Christensen BC, Avissar-Whiting M, Ouellet LG, et al (2010). Mature miRNA sequence polymorphism in MIR196A2 is associated with risk and prognosis of head and neck cancer. Clin Cancer Res, 16, 3713-20.
  6. Chu H, Wang M, Shi D, et al (2011). Hsa-miR-196a2 Rs11614913 Polymorphism Contributes to cancer susceptibility: evidence from 15 case-control Studies. PLoS ONE, 6, 18108.
  7. Du W, Ma XL, Zhao C, et al (2014). Associations of single nucleotide polymorphisms in miR-146a, miR-196a, miR-149 and miR-499 with colorectal cancer susceptibility. Asian Pac J Cancer Prev, 15, 1047-55.
  8. Duan S, Mi S, Zhang W, Dolan ME (2009). Comprehensive analysis of the impact of SNPs and CNVs on human microRNAs and their regulatory genes. RNA Biol, 6, 412-25.
  9. Esquela-Kerscher A, Slack FJ (2006). Oncomirs -microRNAs with a role in cancer. Nature Rev Cancer, 6, 259-69.
  10. Feng W, Ma YL, Zhang P, et al (2012). A genetic variant in microRNA-196a2 is associated with increased cancer risk: a meta-analysis. Mol Biol Rep, 39, 269-75.
  11. George PG, Gangwar R, Mandal RK, et al (2011). Genetic variation in microRNA genes and prostate cancer risk in North Indian population. Mol Biol Rep, 38, 1609-15.
  12. Guo H, Wang K, Xiong G, et al (2010). A functional variant in microRNA-146a is associated with risk of esophageal squamous cell carcinoma in Chinese Han. Fam Cancer, 9, 599-603.
  13. Hamada JI, Omatsu T, Okada F et al (2001). Overexpression of Homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer. Int J Cancer, 93, 516-25.
  14. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70.
  15. Hao YX, Wang JP, Zhao LF (2013). Associations between three common microRNA polymorphisms and hepatocellular carcinoma risk in Chinese. Asian Pac J Cancer Prev, 14, 6601-4.
  16. He B, Pan Y, Cho WC, et al (2012). The association between four genetics variants in microRNAs (rs11614913, rs2910164, rs376444, rs2292832) and cancer risk: evidence from published studies. PLoS ONE, 7, 49032.
  17. Hezova R, Kovarikova A, Bienertova-Vasku J, et al (2012). Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World J Gastroenterol, 18, 2827-31.
  18. Hoffman AE, Zheng T, Yi C, et al (2009). microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res, 69, 5970-7.
  19. Hong YS, Kang HJ, Kwak JY, et al (2011). Association between microrna196a2 rs11614913 genotypes and the risk of nonsmall cell lung cancer in Korean population. J Prev Med Public Health, 44, 125-30.
  20. Hu Z, Chen J, Tian T, et al (2006). Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest, 118, 2600-8.
  21. Kent OA, Mendell JT (2006). A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene, 25, 6188-96.
  22. Kogo R, Mimori K, Tanaka F, Komune S, Mori M (2011). Clinical significance of miR-146a in gastric cancer cases. Clin Cancer Res, 17, 4277-84.
  23. Kumar MS, Lu J, Mercer KL, et al (2007). Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet, 39, 673-7.
  24. Kupcinskas J, Wex T, Link A, et al (2014). Gene polymorphisms of microRNAs in Helicobacter pylori-induced high risk atrophic gastritis and gastric cancer. PLoS ONE, 9, 87467.
  25. Lehmann U, Hasemeier B, Christgen M, et al (2008). Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol, 214, 17-24.
  26. Li L, Sheng Y, Lv L, et al (2013). The association between two microrna variants (mir-499, mir-149) and gastrointestinal cancer risk: a meta-analysis. PLoS ONE, 8, 81967.
  27. Li XD, Li ZG, Song XX, et al (2010). A variant in microRNA-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology, 42, 669-73.
  28. Li YJ, Zhang YZ, Mao YY, et al (2014). A genetic variant in mir-146a modifies digestive system cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 15, 145-50.
  29. Linhares JJ, Azevedo M Jr, Siufi AA, et al (2012). Evaluation of single nucleotide poly morphisms in microRNAs (hsa-miR-196a2 rs11614913 C/T) from Brazilian women with breast cancer. BMC Med Genet, 13, 119.
  30. Long XJ, Lin S, Sun YN, Zheng ZF (2012). Diabetes mellitus and prostate cancer risk in Asian countries: a meta-analysis. Asian Pac J Cancer Prev, 13, 4097-100.
  31. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, et al (2005). MicroRNA expression profiles classify human cancers. Nature, 435, 834-8.
  32. Lu K, Song XL, Han SL, Wang CH, Zhong N, Qi LF (2014). Potential study perspectives on mechanisms and correlations between adiposity and malignancy. Asian Pac J Cancer Prev, 15, 1057-6 0.
  33. Lu L, Katsaros D, de la Longrais IA, Sochirca O, Yu H (2007). Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res, 67, 10117-22.
  34. Ma XP, Zhang T, Peng B, et al (2013). Association between microRNA Polymorphisms and Cancer Risk Based on the Findings of 66 Case- Control Studies. PLoS ONE, 8, 79584.
  35. McGrowder DA, Jackson LA, Crawford TV (2012). Prostate cancer and metabolic syndrome: is there a link? Asian Pac J Cancer Prev, 13, 1-13.
  36. Miller GJ, Miller HL, van Bokhoven A, et al (2003). Aberrant HOXC expression accompanies the malignant phenotype in human prostate. Cancer Res, 63, 5879-88.
  37. Oda K, Tanaka N, Arai T, et al (2007). Polymorphisms in proand anti-inflammatory cytokine genes and susceptibility to atherosclerosis a pathological study of 1503 consecutive autopsy cases. Hum Mol Genet, 16, 592-9.
  38. Okubo M, Tahara T, Shibata T, et al (2010). Association between common genetic variants in Pre-microRNAs and gastric cancer risk in Japanese population. Helicobacter, 15, 524-31.
  39. Okubo M, Tahara T, Shibata T, et al (2010). Association between common genetic variants in pre-microRNAs and the clinicopathological characteristics and survival of gastric cancer patients. Exp Ther Med, 1, 1035-40.
  40. Peng S, Kuang Z, Sheng C, et al (2010). Association of microRNA-196a-2 gene polymorphism with gastric cancer risk in a Chinese population. Dig Dis Sci, 55, 2288-93.
  41. Permuth-Wey J, Thompson RC, Nabors B, et al (2011). A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma. J Neurooncol, 105, 639-46.
  42. Pillai RS, Bhattacharyya SN, Artus CG, et al (2005). Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science, 309, 1573-6.
  43. Qi P, Dou TH, Geng L, et al (2010). Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection. Hum Immunol, 71, 621-6.
  44. Raisch J, Darfeuille-Michaud A, Nguyen HTT (2013). Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol, 19, 2985-96.
  45. Ryan BM, Robles AI, Harris CC (2010). Genetic variation in microRNA networks: the implication for cancer research. Nat Rev Cancer, 10, 389-402.
  46. Saunders MA, Liang H, Li WH (2007). Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA, 104, 3300-5.
  47. Sawabe, M, Arai T, Kasahara I, et al (2004). Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP). Mech Ageing Dev, 125, 547-52.
  48. Shen J, Ambrosome CB, DiCioccio RA, et al (2008). A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis. Carcinogenesis, 29, 1963-6.
  49. Sherr CJ (2004). Principles of tumor suppression. Cell, 116, 235-46.
  50. Srivastava K, Srivastava A (2012). Comprehensive review of genetic association studies and meta-analyses on miRNA polymorphisms and cancer risk. PLoS ONE, 7, 50966.
  51. Sun G, Yan J, Noltner K, Feng J, et al (2009). SNPs in human miRNA genes affect biogenesis and function. RNA, 15, 1640-51.
  52. Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006). NF-$\kappa{B}$-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA, 103, 12481-6.
  53. Takei K, Ikeda S, Arai T, et al (2008). Lympotoxin-alpha polymorphisms and presence of cancer in 1,536 consecutive autopsy cases. BMC Cancer, 8, 235.
  54. Tian T, Shu Y, Chen J, et al (2009). A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomarkers Prev, 18, 1183-7.
  55. Tian T, Xu Y, Dai J, et al (2010). Functional polymorphisms in two pre-microRNAs and cancer risk: a meta-analysis. Int J Mol Epidemiol Genet, 1, 358-66.
  56. Wang J, Bi J, Liu X, et al (2012). Has-miR-146a polymorphism (rs2910164) and cancer risk: meta-analysis of 19 casecontrol studies. Mol Bio Rep, 39, 4571-9.
  57. Wang Z, Cao Y, Jiang C, et al (2012). Lack of association of two common polymorphisms rs2910164 and rs11614913 with susceptibility to hepatocellular carcinoma: a meta-analysis. PLoS ONE, 7, 40039.
  58. Wienholds E, Kloosterman WP, Miska E, et al (2005). MicroRNA expression in zebrafish embryonic development. Science, 309, 310-1.
  59. Woo HY, Park H, Kwon MJ, Chang Y, Ryu S (2012). Association of prostate specific antigen concentration with lifestyle characteristics in Korean men. Asian Pac J Cancer Prev, 13, 5695-9.
  60. Wu D, Wang F, Dai WQ, et al (2013). The miR-146a rs2910164 G > C polymorphism and susceptibility to digestive cancer in Chinese. Asian Pac J Cancer Prev, 14, 399-403.
  61. Xu B, Feng NH, Li PC, et al (2010). A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate, 70, 467-72.
  62. Xu T, Zhu Y, Wei QK, et al (2008). A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis, 29, 2126-31.
  63. Xu W, Xu J, Liu S, et al (2011). Effects of common polymorphisms rs11614913 in miR-196a2 and rs2910164 in miR-146a on cancer susceptibility: a meta-analysis. PLoS ONE, 6, 20471.
  64. Xu Y, Gu L, Pan Y, et al (2013). Different effects of three polymorphisms in MicroRNAs on cancer risk in Asian population: evidence from published literatures. PLoS ONE, 8, 65123.
  65. Ye Y, Wang KK, Gu J, et al (2008). Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk. Cancer Prev Res, 1, 460-9.
  66. Yekta S, Shih IH, Bartel DP (2004). MicroRNA- directed cleavage of HOXB8 mRNA. Science, 304, 594-6.
  67. Yuan Z, Zeng X, Yang D, et al (2013). Effects of common polymorphism rs11614913 in hsa-mir-196a2 on lung cancer risk. PLoS ONE, 8, e61047.
  68. Zeng Y, Sun QM, Liu NN, et al (2010). Correlation between pre-miR-146a C/G polymorphism and gastric cancer risk in Chinese population. World J Gastroenterol, 16, 3578-83.
  69. Zhang H, Su YL, Yu H, Qian BY (2012). Meta-Analysis of the Association between Mir-196a-2 Polymorphism and Cancer Susceptibility. Cancer Biol Med, 9, 63-72.
  70. Zhang J, Wang R, Ma YY, et al (2013). Association between single nucleotide polymorphisms in miRNA196a-2 and miRNA146a and susceptibility to hepatocellular carcinoma in a Chinese population. Asian Pac J Cancer Prev, 14, 6427-31.
  71. Zhou J, Ruixue Lv R, Song X, et al (2011). Association between two genetic variants in miRNA and primary liver cancer risk in the Chinese population. DNA Cell Biol, 31, 524-30.

Cited by

  1. Association between a Polymorphism in miR-34b/c and Susceptibility to Cancer - a Meta-analysis vol.15, pp.17, 2014,
  2. Effects of four single nucleotide polymorphisms in microRNA-coding genes on lung cancer risk vol.35, pp.11, 2014,
  3. Effects of Two Common Polymorphisms rs2910164 in miR-146a and rs11614913 in miR-196a2 on Gastric Cancer Susceptibility vol.2015, pp.1687-630X, 2015,
  4. Genetic polymorphism of miR-146a is associated with gastric cancer risk: a meta-analysis vol.26, pp.2, 2015,
  5. MicroRNA gene polymorphisms and the risk of colorectal cancer vol.13, pp.5, 2017,
  6. C/G polymorphism increased the risk of head and neck cancer, but overall cancer risk: an analysis of 89 studies vol.38, pp.1, 2017,
  7. Comprehensive Review of Genetic Association Studies and Meta-Analysis on polymorphisms in microRNAs and Urological Neoplasms Risk vol.8, pp.1, 2018,