Tumor Biology

, Volume 35, Issue 3, pp 2351–2358 | Cite as

Quantitative assessment of the association between microRNA-499 rs3746444 A/G polymorphism and cancer risk

  • Hongzhi Sun
  • Qing Li
  • Tao Yang
  • Wei Wang
Research Article


Many epidemiological studies have evaluated the association between microRNA-499 rs3746444 A/G polymorphism and cancer risk, but published data are still inconclusive. Therefore, we performed a meta-analysis to evaluate the association between microRNA-499 rs3746444 A/G polymorphism and cancer susceptibility. The summary odds ratio (OR) with its 95 % confidence interval (CI) was calculated to evaluate the association. Seventeen case–control studies with a total of 7,974 cancer cases and 9,404 controls were finally included into this meta-analysis. Overall, microRNA-499 rs3746444 A/G polymorphism was significantly associated with increased risk in both the domain model (GG/AG versus AA: OR = 1.17, 95 % CI, 1.03–1.33, P = 0.02) and the heterozygote comparison model (AG versus AA: OR = 1.15, 95 % CI, 1.01–1.32, P = 0.03) when all studies were pooled into the meta-analysis. Subgroup analysis by ethnicity showed that association between microRNA-499 rs3746444 A/G polymorphism and cancer susceptibility was significant in Asians, but not in Caucasians. In the subgroup analysis by cancer types, no risk of breast, liver, or lung cancers were found significantly associated with microRNA-499 rs3746444 A/G polymorphism in any of the genetic models. In summary, this meta-analysis suggests that microRNA-499 rs3746444 A/G polymorphism is associated with increased susceptibility to cancer in Asians. However, more well-designed studies with large sample size are needed to validate this association among different kinds of cancers.


MicroRNA-499 Cancer Single-nucleotide polymorphism Meta-analysis 


Conflict of interest



  1. 1.
    Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell. 2012;149:515–24.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Fabian MR, Sonenberg N. The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nat Struct Mol Biol. 2012;19:586–93.CrossRefPubMedGoogle Scholar
  3. 3.
    Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148:1172–87.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M. MicroRNAs in cancer management. Lancet Oncol. 2012;13:e249–58.CrossRefPubMedGoogle Scholar
  5. 5.
    Torres A, Torres K, Paszkowski T, Jodlowska-Jedrych B, Radomanski T, Ksiazek A, Maciejewski R. Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer. Tumour Biol. 2011;32:769–76.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Ryan BM, Robles AI, Harris CC. Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer. 2010;10:389–402.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13:271–82.PubMedGoogle Scholar
  8. 8.
    Mishra PJ, Bertino JR. MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics. 2009;10:399–416.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Dong LM, Potter JD, White E, Ulrich CM, Cardon LR, Peters U. Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA. 2008;299:2423–36.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Alshatwi AA, Shafi G, Hasan TN, Syed NA, Al-Hazzani AA, Alsaif MA, Alsaif AA. Differential expression profile and genetic variants of microRNAs sequences in breast cancer patients. PLoS One. 2012;7:e30049.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Catucci I, Yang R, Verderio P, Pizzamiglio S, Heesen L, Hemminki K, Sutter C, Wappenschmidt B, Dick M, Arnold N, Bugert P, Niederacher D, Meindl A, Schmutzler RK, Bartram CC, Ficarazzi F, Tizzoni L, Zaffaroni D, Manoukian S, Barile M, Pierotti MA, Radice P, Burwinkel B, Peterlongo P. Evaluation of SNPs in mir-146a, mir196a2 and mir-499 as low-penetrance alleles in german and italian familial breast cancer cases. Hum Mutat. 2010;31:E1052–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Hu Z, Liang J, Wang Z, Tian T, Zhou X, Chen J, Miao R, Wang Y, Wang X, Shen H. Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Hum Mutat. 2009;30:79–84.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhou J, Lv R, Song X, Li D, Hu X, Ying B, Wei Y, Wang L. Association between two genetic variants in miRNA and primary liver cancer risk in the Chinese population. DNA Cell Biol. 2012;31:524–30.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Xiang Y, Fan S, Cao J, Huang S, Zhang LP. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep. 2012;39:7019–23.CrossRefPubMedGoogle Scholar
  15. 15.
    Kim WH, Min KT, Jeon YJ, Kwon CI, Ko KH, Park PW, Hong SP, Rim KS, Kwon SW, Hwang SG, Kim NK. Association study of microRNA polymorphisms with hepatocellular carcinoma in korean population. Gene. 2012;504:92–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Akkiz H, Bayram S, Bekar A, Akgollu E, Uskudar O. Genetic variation in the microRNA-499 gene and hepatocellular carcinoma risk in a Turkish population: lack of any association in a case–control study. Asian Pac J Cancer Prev. 2011;12:3107–12.PubMedGoogle Scholar
  17. 17.
    Vinci S, Gelmini S, Pratesi N, Conti S, Malentacchi F, Simi L, Pazzagli M, Orlando C. Genetic variants in miR-146a, miR-149, miR-196a2, miR-499 and their influence on relative expression in lung cancers. Clin Chem Lab Med. 2011;49:2073–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Ling XX, Li YY, Yang L, Ji WD, Bin XN, Lu JC. Genetic variant in seed region of hsa-miR-499-3p( rs3746444 A > G) increases risk of lung cancer. Chin J Public Health. 2011;27:1105–7. Article in Chinese.Google Scholar
  19. 19.
    Tian T, Shu Y, Chen J, Hu Z, Xu L, Jin G, Liang J, Liu P, Zhou X, Miao R, Ma H, Chen Y, Shen H. A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomarkers Prev. 2009;18:1183–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhou B, Wang K, Wang Y, Xi M, Zhang Z, Song Y, Zhang L. Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma. Mol Carcinog. 2011;50:499–505.CrossRefPubMedGoogle Scholar
  21. 21.
    Mittal RD, Gangwar R, George GP, Mittal T, Kapoor R. Investigative role of pre-microRNAs in bladder cancer patients: a case–control study in north india. DNA Cell Biol. 2011;30:401–6.CrossRefPubMedGoogle Scholar
  22. 22.
    George GP, Gangwar R, Mandal RK, Sankhwar SN, Mittal RD. Genetic variation in microRNA genes and prostate cancer risk in north indian population. Mol Biol Rep. 2011;38:1609–15.CrossRefPubMedGoogle Scholar
  23. 23.
    Okubo M, Tahara T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, Yonemura J, Ishizuka T, Arisawa T, Hirata I. Association between common genetic variants in pre-microRNAs and gastric cancer risk in japanese population. Helicobacter. 2010;15:524–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Salanti G, Amountza G, Ntzani EE, Ioannidis JP. Hardy–Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet. 2005;13:840–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29.CrossRefGoogle Scholar
  26. 26.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMedGoogle Scholar
  27. 27.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRefPubMedGoogle Scholar
  28. 28.
    Min KT, Kim JW, Jeon YJ, Jang MJ, Chong SY, Oh D, Kim NK. Association of the miR-146 ac > g, 149c > t, 196a2c > t, and 499a > g polymorphisms with colorectal cancer in the korean population. Mol Carcinog. 2011. doi: 10.1002/mc.21849.
  29. 29.
    Srivastava K, Srivastava A, Mittal B. Common genetic variants in pre-microRNAs and risk of gallbladder cancer in north Indian population. J Hum Genet. 2010;55:495–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Liu Z, Li G, Wei S, Niu J, El-Naggar AK, Sturgis EM, Wei Q. Genetic variants in selected pre-microRNA genes and the risk of squamous cell carcinoma of the head and neck. Cancer. 2010;116:4753–60.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Wang L, Qian S, Zhi H, Zhang Y, Wang B, Lu Z. The association between hsa-miR-499 t > c polymorphism and cancer risk: a meta-analysis. Gene. 2012;508(1):9–14.CrossRefPubMedGoogle Scholar
  32. 32.
    Kasinski AL, Slack FJ. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer. 2011;11:849–64.CrossRefPubMedGoogle Scholar
  33. 33.
    Yaman Agaoglu F, Kovancilar M, Dizdar Y, Darendeliler E, Holdenrieder S, Dalay N, Gezer U. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biol. 2011;32:583–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Boldin MP, Baltimore D. MicroRNAs, new effectors and regulators of nf-kappab. Immunol Rev. 2012;246:205–20.CrossRefPubMedGoogle Scholar
  35. 35.
    Lian H, Wang L, Zhang J. Increased risk of breast cancer associated with cc genotype of has-miR-146a rs2910164 polymorphism in Europeans. PLoS One. 2012;7:e31615.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Guo J, Jin M, Zhang M, Chen K. A genetic variant in mir-196a2 increased digestive system cancer risks: a meta-analysis of 15 case–control studies. PLoS One. 2012;7:e30585.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Khella HW, White NM, Faragalla H, Gabril M, Boazak M, Dorian D, Khalil B, Antonios H, Bao TT, Pasic MD, Honey RJ, Stewart R, Pace KT, Bjarnason GA, Jewett MA, Yousef GM. Exploring the role of miRNAs in renal cell carcinoma progression and metastasis through bioinformatic and experimental analyses. Tumour Biol. 2012;33:131–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Nair VS, Maeda LS, Ioannidis JP. Clinical outcome prediction by microRNAs in human cancer: a systematic review. J Natl Cancer Inst. 2012;104:528–40.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Department of General Surgery, the First Affiliated HospitalLiaoning Medical UniversityJinzhouChina
  2. 2.Department of Internal Medicine, the Third Affiliated HospitalLiaoning Medical UniversityJinzhouChina

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