Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2021, 165(1):84-89 | DOI: 10.5507/bp.2019.058

SNPs within CHRNA5-A3-B4 and CYP2A6/B6, nicotine metabolite concentrations and nicotine dependence treatment success in smokers

Jaroslav A. Hubaceka, Ivana Kurcovab, Vera Maresovab, Alexandra Pankovac,d, Lenka Stepankovac, Kamila Zvolskac, Vera Lanskae, Eva Kralikovac,d
a Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
b Department of Toxicology and Forensic Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
c Centre for Tobacco-Dependent, 3rd Department of Medicine – Department of Endocrinology and Metabolism, 1st Faculty of Medicine, Charles University and the General University Hospital in Prague, Czech Republic
d Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University and the General University Hospital in Prague, Czech Republic
e Statistical Unit, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Aim: Plasma values of nicotine and its metabolites are highly variable, and this variability has a strong genetic influence. In our study, we analysed the impact of common polymorphisms associated with smoking on the plasma values of nicotine, nicotine metabolites and their ratios and investigated the potential effect of these polymorphisms and nicotine metabolite ratios on the successful treatment of tobacco dependence.

Methods: Five variants (rs16969968, rs6474412, rs578776, rs4105144 and rs3733829) were genotyped in a group of highly dependent adult smokers (n=103). All smokers underwent intensive treatment for tobacco dependence; 33 smokers were still abstinent at the 12-month follow-up.

Results: The rs4105144 (CYP2A6, P<0.005) and rs3733829 (EGLN2, P<0.05) variants were significantly associated with plasma concentrations of 3OH-cotinine and with 3OH-cotinine: cotinine ratios. Similarly, the unweighted gene score was a significant (P<0.05) predictor of both cotinine:nicotine and 3OH-cotinine:cotinine ratios. No associations between the analysed polymorphisms or nicotine metabolite ratios and nicotine abstinence rate were observed.

Conclusion: Although CYP2A6 and EGLN2 polymorphisms were associated with nicotine metabolism ratios, neither these polymorphisms nor the ratios were associated with abstinence rates.

Keywords: nicotine-acetylcholine receptors, EGLN2, CYP2A6/B6, tobacco dependence, smoking, cotinine, hydroxycotinine, intensive treatment, nicotine metabolism

Received: August 7, 2019; Revised: October 8, 2019; Accepted: November 14, 2019; Prepublished online: November 29, 2019; Published: March 12, 2021  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Hubacek, J.A., Kurcova, I., Maresova, V., Pankova, A., Stepankova, L., Zvolska, K., Lanska, V., & Kralikova, E. (2021). SNPs within CHRNA5-A3-B4 and CYP2A6/B6, nicotine metabolite concentrations and nicotine dependence treatment success in smokers. Biomedical papers, 165(1), 84-89. doi: 10.5507/bp.2019.058
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Benowitz NL, Hukkanen J, Jacob P 3rd. Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol 2009;(192):29-60. Go to original source... Go to PubMed...
    2. Ray R, Tyndale RF, Lerman C. Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J Neurogenet 2009;23(3):252-61. Go to original source... Go to PubMed...
    3. Falcone M, Jepson C, Benowitz N, Bergen AW, Pinto A, Wileyto EP, Baldwin D, Tyndale RF, Lerman C, Ray R. Association of the nicotine metabolite ratio and CHRNA5/CHRNA3 polymorphisms with smoking rate among treatment-seeking smokers. Nicotine Tob Res 2011;13(6):498-503. Go to original source... Go to PubMed...
    4. López-Flores LA, Pérez-Rubio G, Falfán-Valencia R. Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction. EXCLI J 2017;16:174-96. Go to PubMed...
    5. Tricker AR. Nicotine metabolism, human drug metabolism polymorphisms, and smoking behaviour. Toxicology 2003;183(1-3):151-73. Go to original source... Go to PubMed...
    6. Raunio H, Rahnasto-Rilla M. CYP2A6: genetics, structure, regulation, and function. Drug Metabol Drug Interact 2012;27(2):73-88. Go to original source... Go to PubMed...
    7. Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Sulem P, Rafnar T, Esko T, Walter S, Gieger C, Rawal R, Mangino M, Prokopenko I, Mägi R, Keskitalo K, Gudjonsdottir IH, Gretarsdottir S, Stefansson H, Thompson JR, Aulchenko YS, Nelis M, Aben KK, den Heijer M, Dirksen A, Ashraf H, Soranzo N, Valdes AM, Steves C, Uitterlinden AG, Hofman A, Tönjes A, Kovacs P, Hottenga JJ, Willemsen G, Vogelzangs N, Döring A, Dahmen N, Nitz B, Pergadia ML, Saez B, De Diego V, Lezcano V, Garcia-Prats MD, Ripatti S, Perola M, Kettunen J, Hartikainen AL, Pouta A, Laitinen J, Isohanni M, Huei-Yi S, Allen M, Krestyaninova M, Hall AS, Jones GT, van Rij AM, Mueller T, Dieplinger B, Haltmayer M, Jonsson S, Matthiasson SE, Oskarsson H, Tyrfingsson T, Kiemeney LA, Mayordomo JI, Lindholt JS, Pedersen JH, Franklin WA, Wolf H, Montgomery GW, Heath AC, Martin NG, Madden PA, Giegling I, Rujescu D, Järvelin MR, Salomaa V, Stumvoll M, Spector TD, Wichmann HE, Metspalu A, Samani NJ, Penninx BW, Oostra BA, Boomsma DI, Tiemeier H, van Duijn CM, Kaprio J, Gulcher JR; ENGAGE Consortium, McCarthy MI, Peltonen L, Thorsteinsdottir U, Stefansson K. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behaviour. Nat Genet 2010;42(5):448-53. Go to original source... Go to PubMed...
    8. Pan L, Yang X, Li S, Jia C. Association of CYP2A6 gene polymorphisms with cigarette consumption: a meta-analysis. Drug Alcohol Depend 2015;149:268-71. Go to original source... Go to PubMed...
    9. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behaviour. Nat Genet 2010;42(5):441-7. Go to original source... Go to PubMed...
    10. Hubacek JA, Pankova A, Stepankova L, Zvolska K, Adamkova V, Lanska V, Kralikova E. SNPs within CHRNA5-A3-B4 and CYP2A6/B6 are associated with smoking dependence but not with tobacco dependence treatment outcomes in the Czech population. Gene 2017;606:35-8. Go to original source... Go to PubMed...
    11. Králíková E, Kme»ová A, ©těpánková L, Zvolská K, Felbrová V, Kulovaná S, Bortlicek Z, Blaha M, Fraser K. Tobacco dependence, the most important cardiovascular risk factor: treatment in the Czech Republic. Physiol Res 2014;63 Suppl 3:S361-8. Go to original source... Go to PubMed...
    12. Kmetova A, Kralikova E, Stepankova L, Zvolska K, Blaha M, Sticha M, Bortlicek Z, Schroeder DR, Croqham IT. Factors associated with weight changes in successful quitters participating in a smoking cessation program. Addict Behav 2014;39(1):239-45. Go to original source... Go to PubMed...
    13. Králíková E, Čeąka R, Pánková A, ©těpánková L, Zvolská K, Felbrová V, Kulovaná S, Zvolský M. [Tobacco dependence treatment guidelines]. Vnitr Lek 2015;61Suppl1:4-15. (In Czech)
    14. Heatherton F, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström test for nicotine dependence: A revision of the Fagerström Tolerance Questionnaire. British J Addictions 1991;86(9):1119-27. Go to original source... Go to PubMed...
    15. Fagerström K. Determinants of tobacco use and renaming the FTND to the Fagerström Test for Cigarette Dependence. Nicotine Tob Res 2012;14(1):75-8. Go to original source... Go to PubMed...
    16. Fiore MC, Jaén CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ, Dorfman SF, Froelicher ES, Goldstein MG, Healton CG, Henderson PN, Heyman RB, Koh HK, Kottke TE, Lando HA, Mecklenburg RE, Mermelstein RJ, Mullen PD, Orleans CT, Robinson L, Stitzer ML, Tommasello AC, Villejo L, Wewers ME, Murray EW, Bennett G, Heishman S, Husten C, Morgan G, Williams C, Christiansen BA, Piper ME, Hasselblad V, Fraser D, Theobald W, Connell M, Leitzke C. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. 2008; May.
    17. West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction 2005;100(3):299-303. Go to original source... Go to PubMed...
    18. West O, Hajek P, McRobbie H. Systematic review of the relationship between the 3-hydroxycotinine/cotinine ratio and cigarette dependence. Psychopharmacology (Berl) 2011;218(2):313-22. Go to original source... Go to PubMed...
    19. Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for DNA extraction from human nucleated cells. Nucleic Acid Res 1988;16(3):1215. Go to original source... Go to PubMed...
    20. Hubacek JA, Lanska V, Adamkova V. Lack of an association between SNPs within the cholinergic receptor genes and smoking behavior in a Czech post-MONICA study. Genet Mol Biol 2014;37(4):625-30. Go to original source... Go to PubMed...
    21. Hubáček JA, Pikhart H, Peasey A, Kubínová R, Bobák M. Nobody is perfect: comparison of the accuracy of PCR-RFLP and KASP™ method for genotyping. ADH1B and FTO polymorphisms as examples. Folia Biol (Praha) 2015;61(4):156-60. Go to PubMed...
    22. Shakleya DM, Huestis MA. Simultaneous and sensitive measurement of nicotine, cotinine, trans-3'-hydroxycotinine and norcotinine in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877(29):3537-42. Go to original source... Go to PubMed...
    23. Hubacek JA. Drug metabolising enzyme polymorphisms in Middle- and Eastern-European Slavic populations. Drug Metabol Drug Interact 2014;29(1):29-36. Go to original source... Go to PubMed...
    24. Loukola A, Buchwald J, Gupta R, Palviainen T, Hällfors J, Tikkanen E, Korhonen T, Ollikainen M, Sarin AP, Ripatti S, Lehtimäki T, Raitakari O, Salomaa V, Rose RJ, Tyndale RF, Kaprio J. A genome-wide association study of a biomarker of nicotine metabolism. PLoS Genet 2015;11(9):e1005498. Go to original source... Go to PubMed...
    25. Salloum NC, Buchalter ELF, Chanani S, Espejo G, Ismail MS, Laine RO, Nageeb M, Srivastava AB, Trapp N, Trillo L, Vance E, Wenzinger M, Hartz SM, David SP, Chen LS. From genes to treatments: a systematic review of the pharmacogenetics in smoking cessation. Pharmacogenomics 2018;19(10):861-71. Go to original source... Go to PubMed...
    26. Malaiyandi V, Sellers EM, Tyndale RF. Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clin Pharmacol Ther 2005;77(3):145-58. Go to original source... Go to PubMed...
    27. Timofeeva MN, McKay JD, Smith GD, Johansson M, Byrnes GB, Chabrier A, Relton C, Ueland PM, Vollset SE, Midttun Ø, Nygård O, Slimani N, Romieu I, Clavel-Chapelon F, Boutron-Ruault MC, Fagherazzi G, Kaaks R, Teucher B, Boeing H, Weikert C, Bueno-de-Mesquita HB, van Gils C, Peeters PH, Agudo A, Barricarte A, Huerta JM, Rodríguez L, Sánchez MJ, Larrañaga N, Khaw KT, Wareham N, Allen NE, Travis RC, Gallo V, Norat T, Krogh V, Masala G, Panico S, Sacerdote C, Tumino R, Trichopoulou A, Lagiou P, Trichopoulos D, Rasmuson T, Hallmans G, Riboli E, Vineis P, Brennan P. Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC. Cancer Epidemiol Biomarkers Prev 2011;20(10):2250-61. Go to original source... Go to PubMed...
    28. Schuit E, Panagiotou OA, Munafò MR, Bennett DA, Bergen AW, David SP. Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers. Cochrane Database Syst Rev 2017;9:CD011823. Go to original source... Go to PubMed...
    29. Bloom AJ, Baker TB, Chen LS, Breslau N, Hatsukami D, Bierut LJ, Goate A. Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. Hum Mol Genet 2014;23(2):555-61. Go to original source... Go to PubMed...
    30. Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF, Grucza RA, Sun L, Duan W, Budde J, Culverhouse RC, Fox L, Hinrichs AL, Steinbach JH, Wu M, Rice JP, Goate AM, Bierut LJ. The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res 2009;69(17):6848-56. Go to original source... Go to PubMed...
    31. Ware JJ, Chen X, Vink J, Loukola A, Minica C, Pool R, Milaneschi Y, Mangino M, Menni C, Chen J, Peterson RE, Auro K, Lyytikäinen LP, Wedenoja J, Stiby AI, Hemani G, Willemsen G, Hottenga JJ, Korhonen T, Heliövaara M, Perola M, Rose RJ, Paternoster L, Timpson N, Wassenaar CA, Zhu AZ, Davey Smith G, Raitakari OT, Lehtimäki T, Kähönen M, Koskinen S, Spector T, Penninx BW, Salomaa V, Boomsma DI, Tyndale RF, Kaprio J, Munafò MR. Genome-wide meta-analysis of cotinine levels in cigarette smokers identifies locus at 4q13.2. Sci Rep 2016;6:20092. Go to original source... Go to PubMed...
    32. Munafò MR, Timofeeva MN, Morris RW, Prieto-Merino D, Sattar N, Brennan P, Johnstone EC, Relton C, Johnson PC, Walther D, Whincup PH, Casas JP, Uhl GR, Vineis P, Padmanabhan S, Jefferis BJ, Amuzu A, Riboli E, Upton MN, Aveyard P, Ebrahim S, Hingorani AD, Watt G, Palmer TM, Timpson NJ; EPIC Study Group, Davey Smith G. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. J Natl Cancer Inst 2012;104(10):740-8. Go to original source... Go to PubMed...
    33. Maroñas O, Latorre A, Dopazo J, Pirmohamed M, Rodríguez-Antona C, Siest G, Carracedo Á, LLerena A. Progres in pharmacogenetics: consortiums and new strategies. Drug Metab Pers Ther 2016;31(1):47-54. Go to original source...
    34. Rodríguez Vicente AE, Herrero Cervera MJ, Bernal ML, Rojas L, Peiró AM. Personalized medicine into health national services: barriers and potentialities. Drug Metab Pers Ther 2018;33:159-63. Go to original source... Go to PubMed...

    This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.


    Return to the content