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Association of NRG3 and ERBB4 gene polymorphism with nicotine dependence in Turkish population

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Abstract

Background

Nicotine dependence (ND) is characterized by regular smoking, anxiety, irritation, difficulty concentrating, impatience, restlessness, tremor, dizziness, hunger, nicotine demand, and the individual’s reluctance to quit despite knowing the health risks of smoking. Recently, it has been reported that the Neuregulin 3 (NRG3)/Erb-B2 receptor tyrosine kinase 4 (ERBB4) signaling pathway plays a role in ND. NRG3, which is activated after nicotine intake, binds to ERBB4 and causes GABA release. GABA reduces anxiety and tension, which are one of the nicotine withdrawal symptoms. Therefore we aimed to investigate the relationship between NRG3 and ERBB4 gene polymorphisms and ND.

Materials and methods

The study population was comprised of patients with ND (n = 200) and healthy non-smoker control subjects (n = 200) who were matched for age, sex, and compared for comorbidity factors such as alcohol, smoking, duration, and education (age range 18–60). Genotypes were detected by Real-Time PCR using TaqMan technology. The Fagerström Nicotine Dependence Test (FTND) score was 5 and above for the patient group and 0 for the control group. DNA was obtained from whole peripheral blood and six polymorphisms of Neuregulin 3 (NRG3) (rs1836724, rs7562566, and rs10048757) and Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) (rs1764072, rs6584400, and rs10883934) genes were analyzed by real-time PCR method.

Results

Our findings show that the six selected SNPs are not significantly associated with ND in the Turkish population and no correlation with dependence levels (p > 0.05).

Conclusion

Although our findings do not show a relationship between ND and these polymorphisms, it is the first study to investigate these single nucleotide polymorphisms (SNPs) for the first time in ND and to find some genotypes in the Turkish population when compared to other populations. Also, our findings are important in terms of their contribution to the literature and forensic genetics.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Quach BC, Bray MJ, Gaddis NC, Liu M, Palviainen T, Minica CC, Zellers S, Sherva R, Aliev F, Nothnagel M (2020) Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits. Nat Commun 11(1):1–13

    Article  Google Scholar 

  2. Bidwell L, Palmer R, Brick L, McGeary J, Knopik V (2016) Genome-wide SNP heritability of nicotine dependence as a multidimensional phenotype. Psychol Med 46(10):2059

    Article  CAS  Google Scholar 

  3. Kong X, Deng H, Alston T, Kong Y, Wang J (2017) Association of opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with nicotine dependence. Oncotarget 8(48):84329

    Article  Google Scholar 

  4. Romeo-Stuppy K, Dorado D, Bressler D, Sy D, Hausner A (2020) WHO FCTC Article 19: Using the judicial system to fight tobacco. Tob Induc Dis 18:99

    PubMed  PubMed Central  Google Scholar 

  5. Nadalin S, Flego V, Pavlić SD, Volarić D, Badovinac AR, Kapović M, Ristić S (2020) Association between the ACE-I/D polymorphism and nicotine dependence amongst patients with lung cancer. Biomed Rep 13(6):1–1

    Article  Google Scholar 

  6. Loukola A, Wedenoja J, Keskitalo-Vuokko K, Broms U, Korhonen T, Ripatti S, Sarin A-P, Pitkäniemi J, He L, Häppölä A (2014) Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample. Mol Psychiatry 19(5):615–624

    Article  CAS  Google Scholar 

  7. Turner JR, Ray R, Lee B, Everett L, Xiang J, Jepson C, Kaestner KH, Lerman C, Blendy JA (2014) Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Mol Psychiatry 19(7):801–810

    Article  CAS  Google Scholar 

  8. Fisher ML, Loukola A, Kaprio J, Turner JR (2015) Role of the neuregulin signaling pathway in nicotine dependence and co-morbid disorders. Int Rev Neurobiol 124:113–131

    Article  CAS  Google Scholar 

  9. Gupta R, Qaiser B, He L, Hiekkalinna T, Zheutlin A, Therman S, Ollikainen M, Ripatti S, Perola M, Salomaa V (2017) Neuregulin signaling pathway in smoking behavior. Transl Psychiatry 7(8):e1212–e1212

    Article  CAS  Google Scholar 

  10. Noguchi S, Inoue M, Ichikawa T, Kurozumi K, Matsumoto Y, Nakamoto Y, Akiyoshi H, Kamishina H (2021) The NRG3/ERBB4 signaling cascade as a novel therapeutic target for canine glioma. Exp Cell Res 400(2):112504

    Article  CAS  Google Scholar 

  11. Mei L, Nave K-A (2014) Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron 83(1):27–49

    Article  CAS  Google Scholar 

  12. Benowitz NL (2009) Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol 49:57–71

    Article  CAS  Google Scholar 

  13. Zhou L, Fisher ML, Cole RD, Gould TJ, Parikh V, Ortinski PI, Turner JR (2018) Neuregulin 3 signaling mediates nicotine-dependent synaptic plasticity in the orbitofrontal cortex and cognition. Neuropsychopharmacology 43(6):1343–1354

    Article  CAS  Google Scholar 

  14. Fagerstrom K-O, Schneider NG (1989) Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J Behav Med 12(2):159–182

    Article  CAS  Google Scholar 

  15. Miller SA, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215

    Article  CAS  Google Scholar 

  16. De Ruyck K, Nackaerts K, Beels L, Werbrouck J, De Volder A, Meysman M, Salhi B, Van Meerbeeck J, Thierens H (2010) Genetic variation in three candidate genes and nicotine dependence, withdrawal and smoking cessation in hospitalized patients. Pharmacogenomics 11(8):1053–1063

    Article  Google Scholar 

  17. Tang SM, Loke AY (2013) Smoking initiation and personal characteristics of secondary students in Hong Kong. J Adv Nurs 69(7):1595–1606

    Article  Google Scholar 

  18. Kandel DB, Hu MC, Griesler PC, Schaffran C (2007) On the development of nicotine dependence in adolescence. Drug Alcohol Depend 91(1):26–39

    Article  CAS  Google Scholar 

  19. MacLeod SL, Chowdhury P (2006) The genetics of nicotine dependence: relationship to pancreatic cancer. World J Gastroenterol WJG 12(46):7433

    Article  CAS  Google Scholar 

  20. Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA (2004) Nicotine dependence and psychiatric disorders in the united states: results from the national epidemiologic survey on alcohol and relatedconditions. Arch Gen Psychiatry 61(11):1107–1115

    Article  Google Scholar 

  21. Prochaska JJ, Benowitz NL (2016) The past, present, and future of nicotine addiction therapy. Annu Rev Med 67:467–486

    Article  CAS  Google Scholar 

  22. Wise RA, Robble MA (2020) Dopamine and addiction. Annu Rev Psychol 71:79–106

    Article  Google Scholar 

  23. Liu W, Li MD (2018) Insights into nicotinic receptor signaling in nicotine addiction: implications for prevention and treatment. Curr Neuropharmacol 16(4):350–370

    Article  CAS  Google Scholar 

  24. Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154(2):299–315

    Article  CAS  Google Scholar 

  25. Lanza ST, Vasilenko SA (2015) New methods shed light on age of onset as a risk factor for nicotine dependence. Addict Behav 50:161–164

    Article  Google Scholar 

  26. Ali FRM, Agaku IT, Sharapova SR, Reimels EA, Homa DM (2020) Peer reviewed: onset of regular smoking before age 21 and subsequent nicotine dependence and cessation behavior among US adult smokers. Prev Chron Dis 17:E06

    Google Scholar 

  27. Papathanasiou G, Mamali A, Papafloratos S, Zerva E (2014) Effects of smoking on cardiovascular function: the role of nicotine and carbon monoxide. Health Sci J 8(2):274

    Google Scholar 

  28. Li Ming D (2016) Converging findings from linkage and association analyses on susceptibility genes for smoking addiction. In: Tobacco smoking addiction: epidemiology, genetics, mechanisms, and treatment. Springer, Singapore, pp 153–181

  29. Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE (2008) Genetics of nicotine dependence and pharmacotherapy. Biochem Pharmacol 75(1):178–195

    Article  CAS  Google Scholar 

  30. Gold AB, Lerman C (2012) Pharmacogenetics of smoking cessation: role of nicotine target and metabolism genes. Hum Genet 131(6):857–876

    Article  CAS  Google Scholar 

  31. Karakulah K, Sengul C, Sengul CB (2014) Genetics of Smoking addiction/sigara bagimliliginin genetigi. Psikiyatride Guncel Yaklasimlar/Curr Approaches Psychiatry 6(3):284–294

    Google Scholar 

  32. Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30

    Article  CAS  Google Scholar 

  33. Fisher M (2019) Investigating the neural correlates of nicotine withdrawal phenotypes in mice: involvement of CREB-dependent NRG3-ErbB4 signaling in mediating anxiety-like behavior. Doctoral dissertation, University of South Carolina

  34. Alaoui-Jamali MA, Morand GB, da Silva SD (2015) ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics. Front Genet 6:17

    Article  Google Scholar 

  35. Starr A, Greif J, Vexler A, Ashkenazy-Voghera M, Gladesh V, Rubin C, Kerber G, Marmor S, Lev-Ari S, Inbar M (2006) ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy. Int J Cancer 119(2):269–274

    Article  CAS  Google Scholar 

  36. Sasaki H, Okuda K, Kawano O, Endo K, Yukiue H, Yokoyama T, Yano M, Fujii Y (2007) ErbB4 expression and mutation in Japanese patients with lung cancer. Clin Lung Cancer 8(7):429–433

    Article  CAS  Google Scholar 

  37. Kao W-T, Wang Y, Kleinman JE, Lipska BK, Hyde TM, Weinberger DR, Law AJ (2010) Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. Proc Natl Acad Sci 107(35):15619–15624

    Article  CAS  Google Scholar 

  38. Gu F, He Y, Mao Y, Lu S, Zhao C, Li X, Zhou C, Hirsch FR (2019) Risk factors for nicotine dependence in Chinese patients with lung cancer. J Int Med Res 47(1):391–397

    Article  Google Scholar 

  39. Bagheri F, Mesrian Tanha H, Mojtabavi Naeini M, Ghaedi K, Azadeh M (2016) Tumor-promoting function of single nucleotide polymorphism rs1836724 (C3388T) alters multiple potential legitimate microRNA binding sites at the 3’-untranslated region of ErbB4 in breast cancer. Mol Med Rep 13(5):4494–4498

    Article  CAS  Google Scholar 

  40. Wei P, Li L, Zhang Z, Zhang W, Liu M, Sheng X (2018) A genetic variant of miR-335 binding site in the ERBB4 3′-UTR is associated with prognosis of ovary cancer. J Cell Biochem 119(7):5135–5142

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Green Crescent and Mersin University Scientific Research Project Unit for supporting this study as a project coded BAP-SBE TBB (HG) 2014-4 YL.

Funding

This research has not been supported by any institution or organization.

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Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Ege University, 35100, Izmir, Turkey

    Hale Güler Kara

  2. Department of Medical Biology, Faculty of Medicine, Mersin University, 33343, Mersin, Turkey

    Mehmet Emin Erdal

  3. Department of Nutrition and Dietetics, Faculty of Health Sciences, Gaziantep University, Gaziantep, Turkey

    Senay Görücü Yılmaz

  4. Psychiatry Clinic, Denizli, Turkey

    Cem Şengül, Ceyhan Balcı Şengül & Kamuran Karakülah

  5. Unye State Hospital, Ordu, Turkey

    Hale Güler Kara, Mehmet Emin Erdal, Senay Görücü Yılmaz, Cem Şengül, Ceyhan Balcı Şengül & Kamuran Karakülah

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  1. Hale Güler Kara
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Contributions

HGK: Study Design, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing, Statistical calculations. MEE: Study Design, Sampling condition, Methodology, Laboratory design, Manipulation, Writing- review & editing. ŞGY: Study Design, Sampling condition, Methodology, Laboratory design, Manipulation, Writing- review & editing. CŞ: Diagnosis, Data collection, Biochemical Analysis, Writing- review & editing. CBŞ: Data collection, Data Analysis, Writing- review & editing. KK: Statistical Analysis, Writing- review & editing.

Corresponding author

Correspondence to Hale Güler Kara.

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The authors declare that there is no conflict of interest.

Ethical approval

The work described in this article has been carried out by The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; Uniform Requirements for manuscripts submitted to biomedical journals. Approval was obtained from the Mersin University Faculty of Medicine Clinical Research Ethics Committee for our study.

Informed consent

The study consent form was obtained from all voluntary participants. Consent for publication Written informed consent was obtained from all patients before the study.

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Kara, H.G., Erdal, M.E., Yılmaz, S.G. et al. Association of NRG3 and ERBB4 gene polymorphism with nicotine dependence in Turkish population. Mol Biol Rep 48, 5319–5326 (2021). https://doi.org/10.1007/s11033-021-06548-x

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  • DOI: https://doi.org/10.1007/s11033-021-06548-x

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