Molecular Biology Reports

, Volume 40, Issue 10, pp 6027–6033 | Cite as

Association between SNPs in microRNA-machinery genes and tuberculosis susceptibility in Chinese Tibetan population

  • Xingbo Song
  • Siyue Li
  • MeiLang QuCuo
  • Yi Zhou
  • Xin Hu
  • Juan Zhou
  • Xiaojun Lu
  • Jun Wang
  • Wei Hua
  • Yuanxin Ye
  • Binwu YingEmail author
  • Lanlan WangEmail author


Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis and remains a leading cause of morbidity and mortality caused by infectious agents worldwide. Although our current understanding of the pathogenesis of TB is far from clear, there is a growing body of evidence suggesting a genetic contribution to the etiology of TB. By analyzing 294 TB cases and 287 healthy controls in a Chinese Tibetan population, we used a candidate gene approach to evaluate the association between six single nucleotide polymorphisms (rs10719, rs3757, rs3742330, rs636832, rs7813, and rs3744741) in microRNA machinery genes and TB susceptibility. The genotypic distributions of rs3757 and rs3744741 in controls were not in accordance with the Hardy–Weinberg Equilibrium (P < 0.05). Logistic regression analysis demonstrated that subjects carrying rs3742330 GG genotype had significantly decreased risk for TB than individuals carrying AA genotype [odds ratio (OR) = 0.31, 95 % confidence interval (CI) 0.12–0.75, P = 0.004. Carrying the G allele of rs3742330 was associated with a 27 % decreased risk for TB (95 % CI 0.55–0.97, P = 0.03). However, no significant associations were found for rs10719, rs636832 and rs7813. Computational modeling suggests that the rs3742330 lies within a predicted binding site (seed region) for microRNA-632 (miR-632) and that the G allele alters the affinity of microRNA-mRNA binding by disrupting the local structure of dicer 1, ribonuclease type III (DICER) mRNA, presumably allowing for upregulated DICER expression. Taken together, our data suggest that common genetic variations DICER may influence TB risk, possibly through miR-632-mediated regulation. Replication of our studies in other populations will strengthen our understanding of this association.


microRNA Single Nucleotide Polymorphism Tibetan Tuberculosis DICER 



Single nucleotide polymorphism


High-resolution melting


Hardy–Weinberg equilibrium




Toll-like receptor 2


Vitamin D receptor


Natural resistance associated macrophage protein 1


TAR RNA binding protein


miRNA-induced silencing complexes


Polymerase chain reaction


Shrimp Alkalilne Phosphatase



We gratefully acknowledge all the staff who participated in this study. This work was supported by Grants from National Natural Science Foundation of China (No. 81101326).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11033_2013_2712_MOESM1_ESM.doc (63 kb)
Supplementary material 1 (DOC 63 kb)


  1. 1.
    Dolin PJ, Raviglione MC, Kochi A (1994) Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organ 72(2):213–220PubMedGoogle Scholar
  2. 2.
    WHO (2009) Global tuberculosis control: epidemiology, strategy, financing. WHO ReportGoogle Scholar
  3. 3.
    National Technic Steering Group Of The Epidemiological Sampling Survey For Tuberculosis, Duanmu H (2002) Report on fourth national epidemiological sampling survey of tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi 25(1): 3–7Google Scholar
  4. 4.
    Beall CM (2007) Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA 104(Suppl 1):8655–8660PubMedCrossRefGoogle Scholar
  5. 5.
    Zhao M, Kong QP, Wang HW et al (2009) Mitochondrial genome evidence reveals successful Late Paleolithic settlement on the Tibetan Plateau. Proc Natl Acad Sci USA 106(50):21230–21235PubMedCrossRefGoogle Scholar
  6. 6.
    Yilmaz V, Yentur SP, Saruhan-Direskeneli G (2005) IL-12 and IL-10 polymorphisms and their effects on cytokine production. Cytokine 30(4):188–194PubMedCrossRefGoogle Scholar
  7. 7.
    Inomata S, Shijubo N, Kon S et al (2005) Circulating interleukin-18 and osteopontin are useful to evaluate disease activity in patients with tuberculosis. Cytokine 30(4):203–211PubMedCrossRefGoogle Scholar
  8. 8.
    Xu Q, Tin SK, Sivalingam SP et al (2007) Interleukin-18 promoter gene polymorphisms in Chinese patients with systemic lupus erythematosus: association with CC genotype at position -607. Ann Acad Med Singapore 36(2):91–95PubMedGoogle Scholar
  9. 9.
    Ogus AC, Yoldas B, Ozdemir T et al (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23(2):219–223PubMedCrossRefGoogle Scholar
  10. 10.
    Wilkinson RJ, Llewelyn M, Toossi Z et al (2000) Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 355(9204):618–621PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang W, Shao L, Weng X et al (2005) Variants of the natural resistance-associated macrophage protein 1 gene (NRAMP1) are associated with severe forms of pulmonary tuberculosis. Clin Infect Dis 40(9):1232–1236PubMedCrossRefGoogle Scholar
  12. 12.
    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9(2):102–114PubMedCrossRefGoogle Scholar
  13. 13.
    Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120(1):15–20PubMedCrossRefGoogle Scholar
  14. 14.
    Lee Y, Kim M, Han J et al (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23(20):4051–4060PubMedCrossRefGoogle Scholar
  15. 15.
    Lee Y, Ahn C, Han J et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956):415–419PubMedCrossRefGoogle Scholar
  16. 16.
    Han J, Lee Y, Yeom KH et al (2006) Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125(5):887–901PubMedCrossRefGoogle Scholar
  17. 17.
    Yi R, Qin Y, Macara IG et al (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17(24):3011–3016PubMedCrossRefGoogle Scholar
  18. 18.
    Chendrimada TP, Gregory RI, Kumaraswamy E et al (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436(7051):740–744PubMedCrossRefGoogle Scholar
  19. 19.
    Mourelatos Z, Dostie J, Paushkin S et al (2002) miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev 16(6):720–728PubMedCrossRefGoogle Scholar
  20. 20.
    Peters L, Meister G (2007) Argonaute proteins: mediators of RNA silencing. Mol Cell 26(5):611–623PubMedCrossRefGoogle Scholar
  21. 21.
    Tolia NH, Joshua-Tor L (2007) Slicer and the argonautes. Nat Chem Biol 3(1):36–43PubMedCrossRefGoogle Scholar
  22. 22.
    Liu Y, Wang X, Jiang J et al (2011) Modulation of T cell cytokine production by miR-144* with elevated expression in patients with pulmonary tuberculosis. Mol Immunol 48(9–10):1084–1090PubMedCrossRefGoogle Scholar
  23. 23.
    Guo W, Li JT, Pan X et al (2010) Candidate Mycobacterium tuberculosis genes targeted by human microRNAs. Protein Cell 1(5):419–421PubMedCrossRefGoogle Scholar
  24. 24.
    Saunders MA, Liang H, Li WH (2007) Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 104(9):3300–3305PubMedCrossRefGoogle Scholar
  25. 25.
    Iwai N, Naraba H (2005) Polymorphisms in human pre-miRNAs. Biochem Biophys Res Commun 331(4):1439–1444PubMedCrossRefGoogle Scholar
  26. 26.
    Duan R, Pak C, Jin P (2007) Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16(9):1124–1131PubMedCrossRefGoogle Scholar
  27. 27.
    Liao PY, Lee KH (2010) From SNPs to functional polymorphism: the insight into biotechnology applications. Biochem Eng J 49(2):149–158CrossRefGoogle Scholar
  28. 28.
    Wan D, He M, Wang J et al (2004) Two variants of the human hepatocellular carcinoma-associated HCAP1 gene and their effect on the growth of the human liver cancer cell line Hep3B. Genes Chromosomes Cancer 39(1):48–58Google Scholar
  29. 29.
    Yang H, Dinney CP, Ye Y et al (2008) Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer. Cancer Res 68(7):2530–2537PubMedCrossRefGoogle Scholar
  30. 30.
    Horikawa Y, Wood CG, Yang H et al (2008) Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma. Clin Cancer Res 14(23):7956–7962PubMedCrossRefGoogle Scholar
  31. 31.
    Koesters R, Adams V, Betts D et al (1999) Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence, genomic organization, localization to chromosomal bands 1p34–p35, and expression. Genomics 61(2):210–218Google Scholar
  32. 32.
    Kim JS, Choi YY, Jin G et al (2010) Association of a common AGO1 variant with lung cancer risk: a two-stage case-control study. Mol Carcinog 49(10):913–921PubMedCrossRefGoogle Scholar
  33. 33.
    Lin J, Horikawa Y, Tamboli P et al (2010) Genetic variations in microRNA-related genes are associated with survival and recurrence in patients with renal cell carcinoma. Carcinogenesis 31(10):1805–1812PubMedCrossRefGoogle Scholar
  34. 34.
    Zhou Y, Wang J, Lu X et al (2013) Evaluation of six SNPs of MicroRNA machinery genes and risk of schizophrenia. J Mol Neurosci 49(3):594–599PubMedCrossRefGoogle Scholar
  35. 35.
    Li X, Tian X, Zhang B et al (2012) Variation in dicer gene is associated with increased survival in T-cell lymphoma. PLoS ONE 7(12):e51640PubMedCrossRefGoogle Scholar
  36. 36.
    Persson H, Kvist A, Rego N et al (2011) Identification of new microRNAs in paired normal and tumor breast tissue suggests a dual role for the ERBB2/Her2 gene. Cancer Res 71(1):78–86PubMedCrossRefGoogle Scholar
  37. 37.
    Friedlander MR, Mackowiak SD, Li N et al (2012) miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Res 40(1):37–52PubMedCrossRefGoogle Scholar
  38. 38.
    Clague J, Lippman SM, Yang H et al (2010) Genetic Variation in MicroRNA Genes and Risk of Oral Premalignant Lesions. Mol Carcinog 49(2):183–189PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Xingbo Song
    • 1
  • Siyue Li
    • 1
  • MeiLang QuCuo
    • 1
  • Yi Zhou
    • 1
  • Xin Hu
    • 1
  • Juan Zhou
    • 1
  • Xiaojun Lu
    • 1
  • Jun Wang
    • 1
  • Wei Hua
    • 1
  • Yuanxin Ye
    • 1
  • Binwu Ying
    • 1
    Email author
  • Lanlan Wang
    • 1
    Email author
  1. 1.Department of Laboratory MedicineWest China Hospital, Sichuan UniversityChengduPeople’s Republic China

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