Skip to main content
SpringerLink
Log in

The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Inter-individual variations in the genes encoding xenobiotic-metabolizing enzymes have been reported to alter susceptibility to various diseases involving hematological disorders. The purpose of this case–control study was to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing BCR-ABL1 negative myeloproliferative neoplasms (MPN). PCR-RFLP was used for genotyping single nucleotide polymorphisms (SNP) in CYP2D6 and GSTP1 in 139 patients with MPN and 126 controls. There was a significantly increased risk for developing BCR-ABL1 negative MPN for the group bearing the CYP2D6*4 variant allele (X2: 4.487; OR 1.738; 95% CI 1.040–2.904; p = 0.034). The platelet count was higher in CYP2D6*4 allele carriers (p = 0.047). There was no association between the GSTP1 Ile105Val polymorphism and the risk of developing MPNs. MPN patients bearing the GSTP1 Ile105Val variant allele had a higher prevalence of bleeding complications (X2: 7.510; OR 4.635; 95% CI 1.466–14.650; p = 0.006). Our study provides new data that the CYP2D6*4 polymorphism may be associated with an increased risk to develop MPNs while the GSTP1 Ile105Val polymorphism does not show such an association. To our knowledge, the current study is the first to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing MPNs in the Turkish population. Further studies with more patients and controls are needed to support our data.

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

Similar content being viewed by others

Abbreviations

MPN:

Myeloproliferative neoplasm

CYP2D6:

Cytochrome P450 2D6

GSTP1:

Glutathione S-transferase P1

SNP:

Single nucleotide polymorphism

PCR-RFLP:

Polymerase chain reaction-restriction fragment length analysis

PV:

Polycythemia vera

ET:

Essential thrombocytosis

PMF:

Primary myelofibrosis

JAK:

Janus kinase

CALR:

Calreticulin

CYP:

Cytochrome P450

GST:

Glutathione S-transferase

LDH:

Lactate dehydrogenase

Hb:

Hemoglobin

HWE:

Hardy–Weinberg equilibrium

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

CLL:

Chronic lymphocytic leukemia

CML:

Chronic myeloid leukemia

References

  1. Kim J, Haddad RY, Atallah E (2012) Myeloproliferative neoplasms. Dis Mon 58(4):177–194

    Article  Google Scholar 

  2. Koppikar P, Levine RL (2008) JAK2 and MPL mutations in myeloproliferative neoplasms. Acta Haematol 119(4):218–225

    Article  CAS  Google Scholar 

  3. Harrison DA (2012) The JAK/STAT pathway. Cold Spring Harb Perspect Biol 4(3):a011205

    Article  Google Scholar 

  4. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 434(7037):1144–1148

    Article  CAS  Google Scholar 

  5. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061

    Article  CAS  Google Scholar 

  6. Shide K, Shimoda HK, Kumano T, Karube K, Kameda T, Takenaka K et al (2008) Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia 22(1):87–95

    Article  CAS  Google Scholar 

  7. Kim SY, Im K, Park SN, Kwon J, Kim JA, Lee DS (2015) CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis, essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable. Am J Clin Pathol 143(5):635–644

    Article  CAS  Google Scholar 

  8. Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L et al (2014) Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 124:2507–2513

    Article  CAS  Google Scholar 

  9. Roberts-Thomson IC, Butler WJ, Ryan P (1999) Meat, metabolic genotypes and risk for colorectal cancer. Eur J Cancer Prev 8:207–211

    Article  CAS  Google Scholar 

  10. Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE et al (2018) The pharmacogene variation (PharmVar) consortium: incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther 103:399–401

    Article  CAS  Google Scholar 

  11. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M et al (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347:773–776

    Article  CAS  Google Scholar 

  12. Strange RC, Lear JT, Fryer AA (1998) Glutathione S-transferase polymorphisms: influence on susceptibility to cancer. Chem Biol Interact 24(111–112):351–364

    Article  Google Scholar 

  13. Landi S (2000) Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res 463:247–283

    Article  CAS  Google Scholar 

  14. Johansson AS, Stenberg G, Widersten M, Mannervik B (1998) Structure–activity relationships and thermal stability of human glutathione transferase P1–1 governed by the H-site residue 105. J Mol Biol 278:687–698

    Article  CAS  Google Scholar 

  15. Hayes JD, Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 64:154–166

    Article  Google Scholar 

  16. Krajinovic M, Labuda D, Sinnett D (2001) Childhood acute lymphoblastic leukemia: genetic determinants of susceptibility and disease outcome. Rev Environ Health 16(4):263–279

    Article  CAS  Google Scholar 

  17. Nida S, Javid B, Akbar M, Idrees S, Adil W, Ahmad GB (2017) Gene variants of CYP1A1 and CYP2D6 and the risk of childhood acute lymphoblastic leukaemia; outcome of a case control study from Kashmir. India Mol Biol Res Commun 6(2):77–84

    CAS  PubMed  Google Scholar 

  18. Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22(1):14–22

    Article  CAS  Google Scholar 

  19. Thiele J, Kvasnicka HM, Facchetti F, Franco V, Orazi A (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90:1128–1132

    PubMed  Google Scholar 

  20. Schur BC, Bjerke J, Nuwayhid N, Wong SH (2001) Genotyping of cytochrome P450 2D6*3 and *4 mutations using conventional PCR*. Clin Chim Acta 308(1–2):25–31

    Article  CAS  Google Scholar 

  21. Hohaus S, Di Ruscio A, Di Febo A, Massini G, D’Alo F, Guidi F et al (2005) Glutathione S-transferase P1 genotype and prognosis in Hodgkin’s lymphoma. Clin Cancer Res 11:2175–2179

    Article  CAS  Google Scholar 

  22. Infante-Rivard C, Labuda D, Krajinovic M, Sinnett D (1999) Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology 10:481–487

    Article  CAS  Google Scholar 

  23. Raunio H, Kuusisto M, Juvonen RO, Pentikäinen OT (2015) Modeling of interactions between xenobiotics and cytochrome P450 (CYP) enzymes. Front Pharmacol 6:123

    Article  Google Scholar 

  24. Dinama O, Warren AM, Kulkarni J (2014) The role of pharmacogenomic testing in psychiatry: Real world examples. Aust N Z J Psychiatry 48(8):778

    Article  Google Scholar 

  25. Ferri GM, Guastadisegno CM, Intranuovo G, Cavone D, Birtolo F, Cecinati V et al (2018) Maternal exposure to pesticides, paternal occupation in the army/police force, and CYP2D6*4 polymorphism in the etiology of childhood acute leukemia. J Pediatr Hematol Oncol 40(4):e207–e214

    Article  CAS  Google Scholar 

  26. Sayitoglu MA, Hatirnaz O, Erensoy N, Ozbek U (2006) Role of CYP2D6, CYP1A1, CYP2E1, GSTT1 and GSTM1 genes in the susceptibility to acute leukemias. Am J Hematol 81:162–170

    Article  Google Scholar 

  27. Okat Z, Uçar Çiftçi K, Yaman K, Toplayıcı S, Kurt E, Taga Y (2018) CYP 2D6*4 polymorphism in polycythemia vera patients in Turkish population. Marmara Med Jl 31:61–67

    Google Scholar 

  28. Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contributions of the isoenzymes to cancer chemoprotection and drug resistance. CRC Crit Rev Biochem Mol Biol 30:445–600

    Article  CAS  Google Scholar 

  29. Maggini V, Buda G, Galimberti S, Martino A, Orciuolo E, Marabito F et al (2008) Lack of association of NQO1 and GSTP1 polymorphisms with multiple myeloma risk. Leuk Res 32:988–990

    Article  CAS  Google Scholar 

  30. Gross-Davis CA, Heavner K, Frank AL, Newschaffer C, Klotz J, Santella RM et al (2015) The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms. Int J Environ Res Public Health 12(3):2465–2485

    Article  CAS  Google Scholar 

  31. Yuille M, Condie A, Hudson C, Kote-Jarai Z, Stone E, Eeles R, Matutes E et al (2002) Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia. Blood 99(11):4216–4218

    Article  CAS  Google Scholar 

  32. Bănescu C, Trifa AP, Voidăzan S, Moldovan VG, Macarie I, Lazar EB et al (2014) CAT, GPX1, MnSOD, GSTM1, GSTT1, and GSTP1 genetic polymorphisms in chronic myeloid leukemia: a case–control study. Oxid Med Cell Longev 2014:875861

    Article  Google Scholar 

  33. Al-Eitan LN, Rababa’h DM, Alkhatib RQ, Khasawneh RH, Aljarrah OA (2016) GSTM1 and GSTP1 genetic polymorphisms and their associations with acute lymphoblastic leukemia susceptibility in a Jordanian population. J Pediatr Hematol Oncol 38(7):223–229

    Article  Google Scholar 

  34. Trifa AP, Bănescu C, Dima D, Bojan AS, Tevet M, Moldovan VG et al (2016) Among a panel of polymorphisms in genes related to oxidative stress, CAT-262 C>T, GPX1 Pro198Leu and GSTP1 Ile105Val influence the risk of developing BCR-ABL negative myeloproliferative neoplasms. Hematology 21(9):520–525

    Article  CAS  Google Scholar 

  35. Ovsepyan VA, Tregubova EV, Luchinin AS, Minaeva NV (2019) Gene polymorphism of xenobiotic biotransformation enzymes in patients with classical Ph-negative myeloproliferative neoplasms. Bull Exp Biol Med 167(6):767–770

    Article  CAS  Google Scholar 

Download references

Funding

This study was financially granted by the Research Fund of İstanbul University Scientific Projects Unit (Project No: BAP/23924).

Author information

Authors and Affiliations

  1. Division of Medical Genetics, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Capa, 34093, Istanbul, Turkey

    Aynur Daglar-Aday

  2. Department of Medical Genetics, Faculty of Medicine, Giresun University, Giresun, Turkey

    Basak Akadam-Teker

  3. Division of Hematology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Ipek Yonal-Hindilerden & Akif Selim Yavuz

  4. Division of Hematology, Department of Internal Medicine, Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey

    Hasan Dermenci

  5. Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Ezgi Sahin

  6. Hematology Clinic, Istanbul Bakırkoy Sadi Konuk Training and Research Hospital, Istanbul, Turkey

    Fehmi Hindilerden

  7. Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey

    Hulya Yilmaz-Aydogan & Oguz Ozturk

Authors
  1. Aynur Daglar-Aday
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basak Akadam-Teker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ipek Yonal-Hindilerden
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hasan Dermenci
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ezgi Sahin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fehmi Hindilerden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hulya Yilmaz-Aydogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Oguz Ozturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akif Selim Yavuz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design—ADA, BAT; data collection and/or processing—ADA, BAT, HD, ES, IYH, ASY; analysis and/or interpretation—ADA, OÖ, HYA; literature search—ADA; writing manuscript—ADA; English language editing—FH.

Corresponding author

Correspondence to Aynur Daglar-Aday.

Ethics declarations

Conflict of interest

No conflict of interest was declared by the authors.

Ethical approval

The ethical approval of this study was obtained from the Clinical Research Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (Decision No: 2012/634-1037: date: April 13th, 2012).

Informed consent

Written and signed informed consent form was obtained from all of the case and control subjects before the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Daglar-Aday, A., Akadam-Teker, B., Yonal-Hindilerden, I. et al. The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms. Mol Biol Rep 47, 7413–7420 (2020). https://doi.org/10.1007/s11033-020-05796-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05796-7

Keywords

Search

Navigation