Skip to main content
SpringerLink
Log in

MDR1 rs1045642 Variant Is Linked with Lower Expression and Extends Overall Survival of Multiple Myeloma: A Hospital-Based Case-Control Study

  • HUMAN GENETICS
  • Published:
Russian Journal of Genetics Aims and scope Submit manuscript

Abstract

Multiple drug resistance 1 (MDR1) gene encodes P-glycoprotein (P-gp), an ATP-dependent drug efflux pump that protects the cells from a wide range of drugs. Several single nucleotide polymorphisms (SNPs) have been linked with the structural and functional aspect of P-gp and with the predisposition to multiple myeloma. Two hundred thirty-one MM patients and 244 healthy controls were included in the present investigation. MDR1 gene polymorphisms (rs1045642, rs1128503 and rs2032582) were genotyped by TaqMan SNP detection assay. Relative expression of the MDR1 gene was quantified by RT-PCR. Distribution of genotypes and alleles of MDR1 gene polymorphisms (rs1045642, rs1128503 and rs2032582) among the MM patients and healthy controls were comparable. TT genotype and minor allele “T” of MDR1 rs1045642 polymorphism were more frequent in survivors than those who died during the follow-up period of 5 years (TT: OR = 0.37, p = 0.01, T: OR = 0.59, p = 0.007). Relative expression of the MDR1 gene was higher in MM patients than in controls (p < 0.0001). MDR1 polymorphisms (rs1045642) were associated with the expression of MDR1 in MM patients and controls. Survival analysis revealed a significant association of the TT genotype with protection from MM death with standard treatment compared to those with the CC genotype. TT genotype of MDR1 rs1045642 polymorphism is associated with lower MDR1 expression and a protective genotype against MM patients’ mortality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

REFERENCES

  1. Bolli, N., Martinelli, G., and Cerchione, C., The molecular pathogenesis of multiple myeloma, Hematol. Rep., 2020, vol. 12, p. 9054. https://doi.org/10.4081/hr.2020.9054

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Heider, M., Nickel, K., Högner, M., et al., Multiple myeloma: molecular pathogenesis and disease evolution, Oncol. Res. Treat., 2021, vol. 44, pp. 672—681. https://doi.org/10.1159/000520312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Huang, J., Chan, S.C., Lok, V., et al., The epidemiological landscape of multiple myeloma: a global cancer registry estimate of disease burden, risk factors, and temporal trends, Lancet Haematol., 2022, vol. 9, pp. e670—e677.

    Article  PubMed  CAS  Google Scholar 

  4. Eriksson, M. and Karlsson, M., Occupational and other environmental factors and multiple myeloma: a population based case-control study, Occup. Environ. Med., 1992, vol. 49, pp. 95—103.

    Article  CAS  Google Scholar 

  5. Alexander, D.D., Mink, P.J., Adami, H.O., et al., Multiple myeloma: a review of the epidemiologic literature, Int. J. Cancer, 2007, vol. 120, suppl. 12, pp. 40—61. https://doi.org/10.1002/ijc.22718

    Article  PubMed  CAS  Google Scholar 

  6. Cowan, A.J., Allen, C., Barac, A., et al., Global burden of multiple myeloma: a systematic analysis for the global burden of disease study, 2016, JAMA Oncol., 2018, vol. 4, pp. 1221—1227. https://doi.org/10.1001/jamaoncol.2018.2128

    Article  PubMed  PubMed Central  Google Scholar 

  7. Schinasi, L.H., Brown, E.E., Camp, N.J., et al., Multiple myeloma and family history of lymphohaematopoietic cancers: results from the International Multiple Myeloma Consortium, Br. J. Haematol., 2016, vol. 175, pp. 87—101. https://doi.org/10.1111/bjh.14199

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bossennec, M., Di Roio, A., Caux, C., et al., MDR1 in immunity: friend or foe?, Oncoimmunology, 2018, vol. 7, р. e1499388. https://doi.org/10.1080/2162402x.2018.1499388

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Germann, U., P-glycoprotein—a mediator of multidrug resistance in tumour cells, Eur. J. Cancer, 1996, vol. 32, pp. 927—944.

    Article  Google Scholar 

  10. Jamroziak, K. and Robak, T., Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies, Hematology, 2004, vol. 9, pp. 91—105.

    Article  PubMed  CAS  Google Scholar 

  11. Brambila-Tapia, A.J.L., MDR1/ABCB1 polymorphisms: functional effects and clinical implications, Rev. Invest. Clin., 2013, vol. 65, pp. 445—454.

    PubMed  Google Scholar 

  12. Campa, D., Sainz, J., Pardini, B., et al., A comprehensive investigation on common polymorphisms in the MDR1/ABCB1 transporter gene and susceptibility to colorectal cancer, PLoS One, 2012, vol. 7, р. e32784. https://doi.org/10.1371/journal.pone.0032784

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Tang, K., Wong, L.P., Lee, E.J.D., et al., Genomic evidence for recent positive selection at the human MDR1 gene locus, Hum. Mol. Genet., 2004, vol. 13, pp. 783—797. https://doi.org/10.1093/hmg/ddh099

    Article  PubMed  CAS  Google Scholar 

  14. Hoffmeyer, S., Burk, O., and Von Richter, O., et al., Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo, Proc. Natl. Acad. Sci., 2000, vol. 97, pp. 3473—3478.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Sakaeda, T., MDR1 genotype-related pharmacokinetics: fact or fiction?, Drug Metab. Pharmacokinet., 2005, vol. 20, pp. 391—414.

    Article  PubMed  CAS  Google Scholar 

  16. Yin, G., Xiao, Z., Ni, Y., et al., Association of MDR1 single-nucleotide polymorphisms and haplotype variants with multiple myeloma in Chinese Jiangsu Han population, Tumor Biol., 2016, vol. 37, pp. 9549—9554.

    Article  CAS  Google Scholar 

  17. Rajkumar, S.V., Dimopoulos, M.A., Palumbo, A., et al., International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma, Lancet Oncol., 2014, vol. 15, pp. e538–e548.

    Article  PubMed  Google Scholar 

  18. Tseng, C.P., Cheng, A.J., Chang, J.T.C., et al., Quantitative analysis of multidrug-resistance MDR1 gene expression in head and neck cancer by real-time RT-PCR, Jpn. J. Cancer Res., 2002, vol. 93, pp. 1230—1236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Song, P., Lamba, J.K., Zhang, L., et al., G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression, J. Clin. Pharmacol., 2006, vol. 46, pp. 373—380.

    Article  PubMed  CAS  Google Scholar 

  20. Hitzl, M., Drescher, S., van der Kuip, H. et al., The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells, Pharmacogenet. Genomics, 2001, vol. 11, pp. 293—298.

    Article  CAS  Google Scholar 

  21. Basmaci, C., Pehlivan, M., Tomatir, A., et al., Effects of TNF, NOS3, MDR1 gene polymorphisms on clinical parameters, prognosis and survival of multiple myeloma cases, Asian Pac. J. Cancer Prev., 2016, vol. 17, pp. 1009—1014.

    Article  PubMed  CAS  Google Scholar 

  22. Drain, S., Catherwood, M.A., Orr, N. et al., ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma. Leuk. Lymphoma, 2009, vol. 50, pp. 566—570.

    Article  PubMed  CAS  Google Scholar 

  23. Drain, S., Flannely, L., Drake, M.B. et al., Multidrug resistance gene expression and ABCB1 SNPs in plasma cell myeloma, Leuk. Res., 2011, vol. 35, pp. 1457—1463.

    Article  PubMed  CAS  Google Scholar 

  24. Buda, G., Maggini, V., Galimberti, S., et al., MDR1 polymorphism influences the outcome of multiple myeloma patients, Br. J. Haematol., 2007, vol. 137, pp. 454—456.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

Authors would like to thank all participants for their support for completion of the project.

Funding

This work was supported by ongoing institutional funding. No additional grants to carry out or direct this particular research were obtained.

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Affiliated Hospital of Nantong University, 226001, Nantong, Jiangsu, China

    Hua Cai, Xinxin Xu, Huoyan Ji, Yingjuan Shi & Xiuying Shi

Authors
  1. Hua Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinxin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huoyan Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingjuan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiuying Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hua Cai.

Ethics declarations

CONFLICT OF INTEREST

The authors declare that they have no conflicts of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The report contains human participants data, and the ethical clearance was obtained from Institutional Human Ethical Committee.

Additional information

Publisher’s Note.

Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary Information

Supplementary Table 1. MDR1 haplotype distribution among the MM patients and healthy controls
Full size table
Supplementary Table 2. MDR1 haplotype distribution among survivors and non-survivours in MM patients
Full size table

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, H., Xu, X., Ji, H. et al. MDR1 rs1045642 Variant Is Linked with Lower Expression and Extends Overall Survival of Multiple Myeloma: A Hospital-Based Case-Control Study. Russ J Genet 59, 1233–1240 (2023). https://doi.org/10.1134/S1022795423110121

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1022795423110121

Keywords:

Search

Navigation