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
This is a preview of subscription content, log in to check access.
Conflicts of interest
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).
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
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
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
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
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
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
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
Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer. 2003;10(1):43–73.CrossRefPubMedGoogle Scholar
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
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
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
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
Fukuda MKY, Hirota T, et al. Genetic polymorphisms of hepatic ABC-transporter in patients with hepatocellular carcinoma. JCT. 2010;1:114–23.CrossRefGoogle Scholar
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
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
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