Tumor Biology

, Volume 36, Issue 9, pp 7007–7015 | Cite as

Genetic polymorphisms of the multidrug resistance 1 gene MDR1 and the risk of hepatocellular carcinoma

  • Zhi-Chao Wang
  • Long-Zi Liu
  • Xin-Yang Liu
  • Jin-Jing Hu
  • Yong-Na Wu
  • Jie-Yi Shi
  • Liu-Xiao Yang
  • Meng Duan
  • Xiao-Ying Wang
  • Jian Zhou
  • Jia Fan
  • Qiang Gao
Research Article


A possible association between multiple drug resistance 1 gene (MDR1) polymorphisms and the risk of developing hepatocellular carcinoma (HCC) is currently under debate, and evidence from various epidemiological studies has yielded controversial results. To derive a more precise estimation of the association between MDR1 polymorphisms and HCC risk, the present meta-analysis was performed. A total of 8 studies containing 11 cohorts with 4407 cases and 4436 controls were included by systematic literature search of EMBASE, PubMed, Web of Science, and CNKI. All polymorphisms were classified as mutant/wild-type alleles. In particular, the variation type, functional impact, and protein domain location of the polymorphisms were assessed and used as stratified indicators. The pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to evaluate the association. Overall, our results suggested that the mutant alleles of the MDR1 gene were associated with a significantly increased risk for HCC under all genetic models (allelic model: OR = 1.28, 95 % CI = 1.20–1.36, P < 0.001; dominant model: OR = 1.27, 95 % CI = 1.16–1.38, P < 0.001; recessive model: OR = 1.59, 95 % CI = 1.36–1.85, P < 0.001). Furthermore, increased risks for HCC were also revealed in stratified analyses by ethnicity, sample size, and quality scores of cohorts as well as variation type, functional impact, and protein domain location of polymorphisms. In conclusion, the present meta-analysis suggested that the presence of MDR1 mutant alleles might be a risk factor for HCC.


Gene polymorphism Hepatocellular carcinoma Meta-analysis Multiple drug resistance 1 gene 


Conflicts of interest


Financial support

This work was supported by the Major Program of NSFC (No. 81030038), National Key Sci-Tech Project (2012ZX10002011-002), National Natural Science Foundation of China (Nos. 81372648, 81272730, 81272725), FANEDD (No. 201183), and Shanghai “Promising Youth Medical Worker” Project (No. 13Y055).

Supplementary material

13277_2015_3407_MOESM1_ESM.docx (32 kb)
Additional file 1 PRISMA 2009 checklist of this systematic review and meta-analysis. (DOCX 32 kb)
13277_2015_3407_MOESM2_ESM.docx (108 kb)
Additional file 2 MDR1 protein sequence annotation from Uniprot website. (DOCX 108 kb)
13277_2015_3407_Fig3_ESM.gif (47 kb)
Additional file 3

Selection of the related studies. (GIF 46 kb)

13277_2015_3407_MOESM3_ESM.tif (791 kb)
High Resolution Image (TIFF 791 kb)
13277_2015_3407_MOESM4_ESM.docx (107 kb)
Additional file 4 List of included studies. (DOCX 106 kb)


  1. 1.
    Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55. doi: 10.1016/S0140-6736(11)61347-0.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi: 10.3322/caac.21208.CrossRefPubMedGoogle Scholar
  3. 3.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76. doi: 10.1053/j.gastro.2007.04.061.CrossRefPubMedGoogle Scholar
  4. 4.
    Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5(9):558–67. doi: 10.1016/S1473-3099(05)70216-4.CrossRefPubMedGoogle Scholar
  5. 5.
    Tanaka M, Katayama F, Kato H, Tanaka H, Wang J, et al. Hepatitis B and C virus infection and hepatocellular carcinoma in China: a review of epidemiology and control measures. J Epidemiol. 2011;21(6):401–16.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wang ZC, Gao Q, Shi JY, Yang LX, Zhou J, et al. Genetic polymorphism of the kinesin-like protein KIF1B gene and the risk of hepatocellular carcinoma. PLoS One. 2013;8(4):e62571. doi: 10.1371/journal.pone.0062571.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dragani TA. Risk of HCC: genetic heterogeneity and complex genetics. J Hepatol. 2010;52(2):252–7. doi: 10.1016/j.jhep.2009.11.015.CrossRefPubMedGoogle Scholar
  8. 8.
    Jiang DK, Sun J, Cao G, Liu Y, Lin D, et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013;45(1):72–5. doi: 10.1038/ng.2483.CrossRefPubMedGoogle Scholar
  9. 9.
    Park EJ, Lee JH, Yu GY, He G, Ali SR, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208. doi: 10.1016/j.cell.2009.12.052.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol. 2012;56(3):704–13. doi: 10.1016/j.jhep.2011.09.020.CrossRefPubMedGoogle Scholar
  11. 11.
    Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology. 2014. doi: 10.1002/hep.27016.PubMedCentralGoogle Scholar
  12. 12.
    Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71:537–92. doi: 10.1146/annurev.biochem.71.102301.093055.CrossRefPubMedGoogle Scholar
  13. 13.
    Szakacs G, Varadi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008;13(9-10):379–93. doi: 10.1016/j.drudis.2007.12.010.CrossRefPubMedGoogle Scholar
  14. 14.
    Ros JE, Libbrecht L, Geuken M, Jansen PL, Roskams TA. High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease. J Pathol. 2003;200(5):553–60. doi: 10.1002/path.1379.CrossRefPubMedGoogle Scholar
  15. 15.
    Ernest S, Rajaraman S, Megyesi J, Bello-Reuss EN. Expression of MDR1 (multidrug resistance) gene and its protein in normal human kidney. Nephron. 1997;77(3):284–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Marchi N, Hallene KL, Kight KM, Cucullo L, Moddel G, et al. Significance of MDR1 and multiple drug resistance in refractory human epileptic brain. BMC Med. 2004;2:37. doi: 10.1186/1741-7015-2-37.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Enokida H, Shiina H, Igawa M, Ogishima T, Kawakami T, et al. CpG hypermethylation of MDR1 gene contributes to the pathogenesis and progression of human prostate cancer. Cancer Res. 2004;64(17):5956–62. doi: 10.1158/0008-5472.CAN-04-0081.CrossRefPubMedGoogle Scholar
  18. 18.
    Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, et al. Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol. 2001;112(2):300–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Batetta B, Mulas MF, Petruzzo P, Putzolu M, Bonatesta RR, et al. Opposite pattern of MDR1 and caveolin-1 gene expression in human atherosclerotic lesions and proliferating human smooth muscle cells. Cell Mol Life Sci. 2001;58(8):1113–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Jamroziak K, Mlynarski W, Balcerczak E, Mistygacz M, Trelinska J, et al. Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol. 2004;72(5):314–21. doi: 10.1111/j.1600-0609.2004.00228.x.CrossRefPubMedGoogle Scholar
  21. 21.
    Kurzawski M, Drozdzik M, Suchy J, Kurzawski G, Bialecka M, et al. Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol. 2005;61(5-6):389–94. doi: 10.1007/s00228-005-0926-5.CrossRefPubMedGoogle Scholar
  22. 22.
    Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer. 2003;10(1):43–73.CrossRefPubMedGoogle Scholar
  23. 23.
    Sohn JW, Lee SY, Lee SJ, Kim EJ, Cha SI, et al. MDR1 polymorphisms predict the response to etoposide-cisplatin combination chemotherapy in small cell lung cancer. Jpn J Clin Oncol. 2006;36(3):137–41. doi: 10.1093/jjco/hyi231.CrossRefPubMedGoogle Scholar
  24. 24.
    Taniguchi S, Mochida Y, Uchiumi T, Tahira T, Hayashi K, et al. Genetic polymorphism at the 5′ regulatory region of multidrug resistance 1 (MDR1) and its association with interindividual variation of expression level in the colon. Mol Cancer Ther. 2003;2(12):1351–9.PubMedGoogle Scholar
  25. 25.
    Wu L, Xu X, Shen J, Xie H, Yu S, et al. MDR1 gene polymorphisms and risk of recurrence in patients with hepatocellular carcinoma after liver transplantation. J Surg Oncol. 2007;96(1):62–8. doi: 10.1002/jso.20774.CrossRefPubMedGoogle Scholar
  26. 26.
    Yu X, Xie H, Wei B, Zhang M, Wang W, et al. Association of MDR1 gene SNPs and haplotypes with the tacrolimus dose requirements in Han Chinese liver transplant recipients. PLoS One. 2011;6(11):e25933. doi: 10.1371/journal.pone.0025933.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004;75(1):13–33. doi: 10.1016/j.clpt.2003.09.012.CrossRefPubMedGoogle Scholar
  28. 28.
    Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003;22(47):7468–85. doi: 10.1038/sj.onc.1206948.CrossRefPubMedGoogle Scholar
  29. 29.
    Chen Y-D, Yang F, Feng S-T, et al. A case-control study on the association between genetic polymorphisms of MDR1 and hepatic cell cancer susceptibility. Chin Clin Oncol. 2009;14(12):1007–81.Google Scholar
  30. 30.
    Fukuda MKY, Hirota T, et al. Genetic polymorphisms of hepatic ABC-transporter in patients with hepatocellular carcinoma. JCT. 2010;1:114–23.CrossRefGoogle Scholar
  31. 31.
    Ren YQ, Han JQ, Cao JB, Li SX, Fan GR. Association of MDR1 gene polymorphisms with susceptibility to hepatocellular carcinoma in the Chinese population. Asian Pac J Cancer Prev. 2012;13(11):5451–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Gao J. Association of MDR1 gene polymorphisms with the risk of hepatocellular carcinoma in the Chinese Han population. Braz J Med Biol Res. 2013;46(3):311–7.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Jing Rui DX, Deng W, et al. Correlation between MDR1 polymorphism and primary liver cancer in Guangxi. Chin J Oncol Prev Treat. 2013;5(2):122–5.Google Scholar
  34. 34.
    Yang D, Zhou F, Wang X, Gao H, Li G, et al. Association analysis between MDR1 gene polymorphisms and risk of hepatocellular carcinoma in Chinese population. Biomarkers. 2013;18(3):236–41. doi: 10.3109/1354750X.2013.773079.CrossRefPubMedGoogle Scholar
  35. 35.
    Li XF, He HB, Zhu YS, He JK, Ye WW, et al. Association between the c.3751G > a genetic variant of MDR1 and hepatocellular carcinoma risk in a Chinese Han population. Asian Pac J Cancer Prev. 2013;14(9):5361–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Wan YY, Wang XW, Hui HX, Wan L. Association between the c.1564A > T genetic polymorphism of the MDR1 gene and hepatocellular carcinoma in Chinese population. Genet Mol Res. 2014;13(3):6820–6. doi: 10.4238/2014.August.29.3.CrossRefPubMedGoogle Scholar
  37. 37.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65–94.CrossRefPubMedGoogle Scholar
  38. 38.
    Gnad F, Baucom A, Mukhyala K, Manning G, Zhang Z. Assessment of computational methods for predicting the effects of missense mutations in human cancers. BMC Genomics. 2013;14 Suppl 3:S7. doi: 10.1186/1471-2164-14-S3-S7.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32(11):1706–12. doi: 10.1007/s00134-006-0327-y.CrossRefPubMedGoogle Scholar
  40. 40.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.CrossRefPubMedGoogle Scholar
  41. 41.
    DerSimonian R. Combining evidence from clinical trials. Anesth Analg. 1990;70(5):475–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Lau J, Ioannidis JP, Terrin N, Schmid CH, Olkin I. The case of the misleading funnel plot. BMJ. 2006;333(7568):597–600. doi: 10.1136/bmj.333.7568.597.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pagani F, Raponi M, Baralle FE. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc Natl Acad Sci U S A. 2005;102(18):6368–72. doi: 10.1073/pnas.0502288102.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet. 2011;12(10):683–91. doi: 10.1038/nrg3051.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Zhi-Chao Wang
    • 1
    • 2
  • Long-Zi Liu
    • 1
    • 2
  • Xin-Yang Liu
    • 3
    • 4
  • Jin-Jing Hu
    • 5
  • Yong-Na Wu
    • 5
  • Jie-Yi Shi
    • 1
    • 2
  • Liu-Xiao Yang
    • 1
    • 2
  • Meng Duan
    • 1
    • 2
  • Xiao-Ying Wang
    • 1
    • 2
  • Jian Zhou
    • 1
    • 2
    • 6
  • Jia Fan
    • 1
    • 2
    • 6
  • Qiang Gao
    • 1
    • 2
  1. 1.Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical CollegeFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Fudan UniversityShanghaiChina
  3. 3.Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
  4. 4.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
  5. 5.Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
  6. 6.Institute of Biomedical SciencesFudan UniversityShanghaiChina

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