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Frequency of the C1236T, G2677T/A and C3435T MDR1 gene polymorphisms in the Serbian population

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Abstract

The multi-drug resistance 1 (MDR1) gene encodes for a P-glycoprotein (PGP), which acts as a gate-keeper against various kinds of xenobiotics. Several single nucleotide polymorphisms (SNPs) in the MDR1 gene that may influence PGP level and function have been identified. The aim of this study was to simultaneously analyze the three most important MDR1 SNPs, C3435T, G2677T/A and C1236T, in the Serbian population and to compare the results with those published for other ethnic groups. A group of 158 unrelated, healthy subjects was included in the present study. For determination of MDR1 SNPs, a multiplexed mutagenically separated PCR was performed. The genotype frequency of the analyzed MDR1 SNPs was as follows: 3435 nt - 0.19 (CC), 0.54 (CT) and 0.27 (TT); 2677 nt - 0.26 (GG), 0.52 (GT), 0.15 (TT), 0.03 (GA) and 0.064 (TA), and 1236 nt - 0.23 (CC), 0.61 (CT) and 0.16 (TT). Our results for the Serbian population could be relevant for further investigation of drugs that are substrates of PGP and for studies of interethnic diversity in MDR1 polymorphism frequency.

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References

  1. Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N et al.: MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 significantly influenced by ethnicity. Pharmacogenetics, 2001, 11, 217–221.

    Article  CAS  PubMed  Google Scholar 

  2. Asano T, Takahashi KA, Fujioka M, Inoue S, Okamoto M, Sugioka N, Nishino H et al.: ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation. Pharmacogenetics, 2003, 13, 675–682.

    Article  CAS  PubMed  Google Scholar 

  3. Bosch TM, Huitema AD, Doodeman VD, Jansen R, Witteveen E, Smit WM, Jansen RL et al.: Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res, 2006, 12, 5786–5793.

    Article  CAS  PubMed  Google Scholar 

  4. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E et al.: Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther, 2001, 69, 169–174.

    Article  CAS  PubMed  Google Scholar 

  5. Cascorbi I, Kroemer HK, Siegmund W: Pharmacogenetics of P-gp mediated drug transport. Nova Acta Leopold, 2003, 329, 93–100.

    Google Scholar 

  6. Cavaco I, Gil JP, Gil-Berglund E, Ribeiro V: CYP3A4 and MDR1 alleles in a Portuguese population. Clin Chem Lab Med, 2003, 41, 1345–1350.

    CAS  PubMed  Google Scholar 

  7. Drozdzik M, Bialecka M, Mysliwiec K, Honczarenko K, Stankiewicz J, Sych Z: Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson’s disease. Pharmacogenetics, 2003, 13, 259–263.

    Article  CAS  PubMed  Google Scholar 

  8. Droździk M, Stefankiewicz J, Kurzawa R, Górnik W, Bączkowski T, Kurzawski M: Association of the MDR1 (ABCB1) gene 3435C>T polymorphism with male infertility. Pharmacol Rep, 2009, 61, 690–696.

    Article  PubMed  Google Scholar 

  9. Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, Decosterd LA et al.: Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet, 2002, 359, 30–36.

    Article  CAS  PubMed  Google Scholar 

  10. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmoller J, Frotschl R, Kopke K, Gerloff T et al.: Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol, 2003, 59, 303–312.

    Article  CAS  PubMed  Google Scholar 

  11. Goreva OB, Grishanova AY, Domnikova NP, Mukhin OV, Lyakhovich VV: MDR1 gene C1236T and C6+139T polymorphisms in the Russian population: associations with predisposition to lymphoproliferative diseases and drug resistance. Bull Exp Biol Med, 2004, 138, 404–406.

    Article  CAS  PubMed  Google Scholar 

  12. Gumus-Akay G, Rustemoglu A, Karadag A, Sunguroglu A: Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population. Genet Mol Res, 2008, 7, 1193–1199.

    Article  CAS  PubMed  Google Scholar 

  13. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T 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 USA, 2000, 97, 3473–3478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Illmer T, Schuler US, Thiede C, Schwartz UI, Kim RB, Gotthard S, Freund D et al.: MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res, 2002, 62, 4955–4962.

    CAS  PubMed  Google Scholar 

  15. Jamroziak K, Młynarski W, Balcerczak E, Mistygacz M, Trelińska J, Mirowski M, Bodalski J, Robak T: Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol, 2004, 72, 314–321.

    Article  CAS  PubMed  Google Scholar 

  16. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ: Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender specific manner. Am J Cardiol, 2004, 93, 1046–1050.

    Article  CAS  PubMed  Google Scholar 

  17. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A et al.: Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther, 2001, 70, 189–199.

    Article  CAS  PubMed  Google Scholar 

  18. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM: A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science, 2007, 315, 525–528.

    Article  CAS  PubMed  Google Scholar 

  19. Komoto C, Nakamura T, Sakaeda T, Kroetz DL, Yamada T, Omatsu H, Koyama T et al.: MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal and esophageal cancer. Drug Metab Pharmacokinet, 2006, 21, 126–132.

    Article  CAS  PubMed  Google Scholar 

  20. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, Stryke D et al.: Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics, 2003, 13, 481–494.

    Article  CAS  PubMed  Google Scholar 

  21. Kurzawski M, Drońdzik M, Suchy J, Kurzawski G, Białecka M, Górnik W, Lubiński J: Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol, 2005, 61, 389–394.

    Article  CAS  PubMed  Google Scholar 

  22. Kurzawski M, Pawlik A, Górnik W, Droździk M: Frequency of common MDR1 gene variants in a Polish population. Pharmacol Rep, 2006, 58, 35–40.

    CAS  PubMed  Google Scholar 

  23. Maeda K, Sugiyama Y: Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs. Drug Metab Pharmacokinet, 2008, 23, 223–235.

    Article  CAS  PubMed  Google Scholar 

  24. Marzolini C, Paus E, Buclin T, Kim RB: Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther, 2004, 75, 13–33.

    Article  CAS  PubMed  Google Scholar 

  25. Mickley LA, Lee JS, Weng Z, Zhan Z, Alvarez M, Wilson W, Bates SE, Fojo T: Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors. Blood, 1998, 91, 1749–1756.

    Article  CAS  PubMed  Google Scholar 

  26. Pauli-Magnus C, Kroetz DL: Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharm Res, 2004, 21, 904–913.

    Article  CAS  PubMed  Google Scholar 

  27. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I, Gawronska-Szklarz B: The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther, 2004, 42, 496–503.

    Article  CAS  PubMed  Google Scholar 

  28. Pechandova K, Buzkova H, Slanar O, Perlik F: Polymorphisms of the MDR1 gene in the Czech population. Folia Biol (Praha), 2006, 52, 184–189.

    CAS  Google Scholar 

  29. Sakurai A, Onishi Y, Hirano H, Seigneuret M, Obanayama K, Kim G, Liew EL et al.: Quantitative structure-activity relationship analysis and molecular dynamics simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1 (P-glycoprotein/MDR1). Biochemistry, 2007, 46, 7678–7693.

    Article  CAS  PubMed  Google Scholar 

  30. Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, Stange E et al.: Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology, 2003, 124, 26–33.

    Article  CAS  PubMed  Google Scholar 

  31. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM: Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med, 2003, 348, 1442–1448.

    Article  CAS  PubMed  Google Scholar 

  32. Siegsmund M, Brinkmann U, Schaffeler E, Weirich G, Schwab M, Eichelbaum M, Fritz P et al.: Association of the P-glycoprotein transporter MDR1 (C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol, 2002, 13, 1847–1854.

    Article  CAS  PubMed  Google Scholar 

  33. Sunder-Plassmann R, Rieger S, Endler G, Brunner M, Mueller M, Mannhalter C: Simultaneous analysis of MDR1 C3435T, G2677T/A, and C1236T genotypes by multiplexed mutagenically separated PCR. Clin Chem Lab Med, 2005, 43, 192–194.

    Article  CAS  PubMed  Google Scholar 

  34. Tang K, Wong LP, Lee EJ, Chong SS, Lee CG: Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum Mol Genet, 2004, 13, 783–797.

    Article  CAS  PubMed  Google Scholar 

  35. Turgut S, Turgut G, Atalay EO: Genotype and allele frequency of human multidrug resistance (MDR1) gene C3435T polymorphism in Denizli province of Turkey. Mol Biol Rep, 2006, 33, 295–300.

    Article  CAS  PubMed  Google Scholar 

  36. Ueda K, Cardarelli C, Gottesman MM, Pastan I: Expression of a full-length cDNA for the human ‘MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA, 1987, 84, 3004–3008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vicente J, Sinues B, Fanlo A, Vasquez P, Medina JC, Martinez-Jarreta B: Polymorphisms of the MDR1 gene in Central Americans and Spaniards. Mol Biol Rep, 2008, 35, 473–478.

    Article  CAS  PubMed  Google Scholar 

  38. Wasilewska A, Zalewski G, Chyczewski L, Zoch-Zwierz W: MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children. Pediatr Nephrol, 2007, 22, 44–51.

    Article  PubMed  Google Scholar 

  39. Zhang Y, Jiang XH, Hu YQ, Li ZR, Su L, Wang ZG, Ma G: MDR1 genotypes do not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic males. Br J Clin Pharmacol, 2008, 66, 247–254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Maja Milojkovic.

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Milojkovic, M., Stojnev, S., Jovanovic, I. et al. Frequency of the C1236T, G2677T/A and C3435T MDR1 gene polymorphisms in the Serbian population. Pharmacol. Rep 63, 808–814 (2011). https://doi.org/10.1016/S1734-1140(11)70593-X

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  • DOI: https://doi.org/10.1016/S1734-1140(11)70593-X

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