Download PDF
J Pediatr Genet 2022; 11(03): 213-220
DOI: 10.1055/s-0041-1723975
Original Article

CYP2D6 rs35742686 and rs3892097 Gene Polymorphisms and Childhood Acute Lymphoblastic Leukemia: Relation to Disease Susceptibility in Kashmiri Children

Nidha Sadiq Shapoo 
1   Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
,
Akbar Masood
1   Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
,
Javid R. Bhat
2   Department of Clinical Haematology, Sher-e-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
,
A. S. Bhatia
3   Department of Biochemistry, Government Medical College, Jammu, Jammu and Kashmir, India
,
Idrees A. Shah
1   Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
,
Bashir A. Ganai
4   Centre of Research for Development, University of Kashmir, Srinagar, Jammu and Kashmir, India
› Author Affiliations Funding The study was financially supported by Department of Science and Technology (DST), Govt. of India, under Women Scientist B (WOS-B) (SoRF) scheme via Letter No. DST/Disha/SoRF/PM/011/2013/C.
› Further Information
    Permissions and Reprints

Abstract

CYP2D6 is one of the most widely investigated CYPs in relation to gene polymorphism. This study analyzed the relationship between CYP2D6 rs35742686 and rs3892097 single-nucleotide polymorphisms (SNPs) and potential risk factors in the development of acute lymphoblastic leukemia (ALL) in Kashmiri children. We recruited 300 cases and 600 controls for genotyping and risk factors assessment. Genotypes of rs35742686 and rs3892097 were analyzed by polymerase chain reaction-restriction fragment length polymorphism method. CYP2D6 expression analysis was done by quantitative reverse transcription polymerase chain reaction in ALL cases. Conditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI). High risk of ALL was observed in cases who carried the mutant genotypes of rs35742686 (OR = 18.15; 95% CI = 4.13–79.66, p < 0.0001) or rs3892097 (OR = 24.06; 95% CI = 10.23–56.53, p < 0.0001). Significant interaction was observed between rs35742686 and rs3892097 SNPs (P interaction = 0.001). The risk associated with the variant genotypes of rs35742686 and rs3892097 was retained in the cases whose fathers were smokers or had maternal X-ray exposure (p < 0.001). Relative messenger ribonucleic acid expression across genotypes was significantly decreased in cases carrying rs357426863 (*3/*3) (n-fold = 0.37 ± 0.156, p < 0.0079) and rs3892097 SNPs (*4/*4) (n-fold = 0.02 ± 0.0075, p < 0.0001) suggesting these two events are independent in ALL cases. The study concluded that rs35742686 and rs3892097 SNPs are significantly associated with ALL risk in Kashmiri children.

Keywords

CYP2D6 - gene polymorphisms - lymphoblastic leukemia - Kashmir


Publication History

Received: 13 August 2020

Accepted: 17 December 2020

Article published online:
19 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013; 381 (9881): 1943-1955
    CrossrefPubMedGoogle Scholar
  • 2 Papaemmanuil E, Hosking FJ, Vijayakrishnan J. et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 2009; 41 (09) 1006-1010
    CrossrefPubMedGoogle Scholar
  • 3 Vijayakrishnan J, Houlston RS. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica 2010; 95 (08) 1405-1414
    CrossrefPubMedGoogle Scholar
  • 4 Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect 2007; 115 (01) 138-145
    CrossrefPubMedGoogle Scholar
  • 5 Anderson LM. Environmental genotoxicants/carcinogens and childhood cancer: bridgeable gaps in scientific knowledge. Mutat Res 2006; 608 (02) 136-156
    CrossrefPubMedGoogle Scholar
  • 6 Tompkins LM, Wallace AD. Mechanisms of cytochrome P450 induction. J Biochem Mol Toxicol 2007; 21 (04) 176-181
    CrossrefPubMedGoogle Scholar
  • 7 Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 1999; 93 (05) 1496-1501
    CrossrefPubMedGoogle Scholar
  • 8 Olshan AF, Weissler MC, Watson MA, Bell DA. GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms, tobacco use, and the risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev 2000; 9 (02) 185-191
    PubMedGoogle Scholar
  • 9 Eichelbaum M, Bertilsson L, Säwe J, Zekorn C. Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin Pharmacol Ther 1982; 31 (02) 184-186
    CrossrefPubMedGoogle Scholar
  • 10 Sim SC, Ingelman-Sundberg M. Update on allele nomenclature for human cytochromes P450 and the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Database. Methods Mol Biol 2013; 987: 251-259
    CrossrefPubMedGoogle Scholar
  • 11 Fareed M, Kaisar Ahmad M, Azeem Anwar M, Afzal M. Impact of consanguineous marriages and degrees of inbreeding on fertility, child mortality, secondary sex ratio, selection intensity, and genetic load: a cross-sectional study from Northern India. Pediatr Res 2017; 81 (1-1): 18-26
    CrossrefPubMedGoogle Scholar
  • 12 Rasool MT, Lone MM, Wani ML, Afroz F, Zaffar S, Mohib-ul Haq M. Cancer in Kashmir, India: burden and pattern of disease. J Cancer Res Ther 2012; 8 (02) 243-246
    CrossrefPubMedGoogle Scholar
  • 13 Nida S, Javid B, Akbar M, Idrees S, Adil W, Ahmad GB. 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 2017; 6 (02) 77-84
    PubMedGoogle Scholar
  • 14 Bennett JM, Catovsky D, Daniel MT. et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33 (04) 451-458
    Google Scholar
  • 15 Arber DA, Orazi A, Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
    Google Scholar
  • 16 Sambrook J, Rusell DW. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 2001
    Google Scholar
  • 17 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25 (04) 402-408
    Google Scholar
  • 18 Łapiński Ł, Agundez JAG, Wiela-Hojeńska A. et al. CYP2D6 gene amplification and the risk of acute myeloblastic leukemia. Pharmacol Rep 2007; 59: 167-172
    PubMedGoogle Scholar
  • 19 Lemos MC, Cabrita FJ, Silva HA, Vivan M, Plácido F, Regateiro FJ. Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis 1999; 20 (07) 1225-1229
    CrossrefPubMedGoogle Scholar
  • 20 Joseph T, Kusumakumary P, Chacko P, Abraham A, Radhakrishna Pillai M. Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children. Pediatr Blood Cancer 2004; 43 (05) 560-567
    CrossrefPubMedGoogle Scholar
  • 21 Aydin-Sayitoglu M, Hatirnaz O, Erensoy N, Ozbek U. Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias. Am J Hematol 2006; 81 (03) 162-170
    CrossrefPubMedGoogle Scholar
  • 22 Silveira VdaS, Canalle R, Scrideli CA, Queiroz RGP, Tone LG. Role of the CYP2D6, EPHX1, MPO, and NQO1 genes in the susceptibility to acute lymphoblastic leukemia in Brazilian children. Environ Mol Mutagen 2010; 51 (01) 48-56
    PubMedGoogle Scholar
  • 23 Llerena A, Dorado P, Ramírez R. et al; CEIBA Consortium of Ibero–American Network of Pharmacogenetics & Pharmacogenomics RIBEF. CYP2D6 -1584C>G promoter polymorphism and debrisoquine ultrarapid hydroxylation in healthy volunteers. Pharmacogenomics 2013; 14 (16) 1973-1977
    CrossrefPubMedGoogle Scholar
  • 24 Jin MW, Xu SM, An Q, Wang P. A review of risk factors for childhood leukemia. Eur Rev Med Pharmacol Sci 2016; 20 (18) 3760-3764
    PubMedGoogle Scholar
  • 25 Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact 2012; 196 (03) 59-67
    CrossrefPubMedGoogle Scholar
  • 26 Bartley K, Metayer C, Selvin S, Ducore J, Buffler P. Diagnostic X-rays and risk of childhood leukaemia. Int J Epidemiol 2010; 39 (06) 1628-1637
    CrossrefPubMedGoogle Scholar
  • 27 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Radiation. IARC Monogr Eval Carcinog Risks Hum 2012; 100 (Pt D): 7-303
    PubMedGoogle Scholar
  • 28 Ribeiro KB, Buffler PA, Metayer C. Socioeconomic status and childhood acute lymphocytic leukemia incidence in São Paulo, Brazil. Int J Cancer 2008; 123 (08) 1907-1912
    CrossrefPubMedGoogle Scholar
  • 29 Braveman PA, Cubbin C, Egerter S. et al. Socioeconomic status in health research: one size does not fit all. JAMA 2005; 294 (22) 2879-2888
    CrossrefPubMedGoogle Scholar