• Leo Rex

The Nicotinic Cholinergic Genes (16)

To read the first article in this series, click here.

To read the previous article in this series, click here.

To watch my accompanying YouTube video to this blog post, click here.


THE NICOTINIC ONCOGENES


The reader will recall from our earlier discussion that there are two categories of nicotinic cholinergic receptor genes – the CHRNAs and the CHRNBs, corresponding to the α and β receptors, respectively. Broadly, the CHRNAs have been repeatedly tied to lung cancer[1][2][3] and other lung diseases such as chronic obstructive[4][5] pulmonary disease and asthma[6][7][8], though always in the context of smoking[9][10]. They have also repeatedly been tied to substance use and addiction[11]. A single gene, CHRNA7, has also been linked to schizophrenia[12] and identified as a potential target for antipsychotic drugs[13], which explains why the α7 receptor-agonizing compound SEN12333 is being studied for the treatment of schizophrenia. But why the strong ties to cancer and lung disease?


Nicotinic cholinergic receptors bind to nicotine as well as 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), the cancer causing derivates of smoking. The nAChRs are also in the lungs, where they bind to both nicotine and NNK and NNN. Disturbingly, NNN, bacon, and processed meats are all nitrosamines, making NNN a carcinogen even when not burned. Moreover, it has an affinity for the nicotinic receptors that is 5,000x times greater than nicotine.


NNK is also found in unburned tobacco and has an affinity for the α7 receptor (the one tied to schizophrenia) that is 1,300x greater than nicotine’s affinity. It is a mutagen that causes polymorphisms in the human genome, such as at the angiotensin II (AT2) gene that is a target of blood pressure medications. Interestingly, cruciferous vegetables and green tea’s EGCG have been shown to inhibit damage arising from NNK.


Nonetheless, the nicotinic cholinergic genes are found at central regulatory loops for numerous cell growth pathways and may act as oncogenes (i.e. cancer promoting genes) at various steps in the developments of tumors[14], from the practice of smoking tobacco.


THE NICOTINIC ADDICTION GENES


In terms of addiction, the nAChR genes have been associated with the habitual use of nicotine, alcohol, cocaine, and opioids. These drugs affect the GABAergic, dopaminergic, and serotonergic systems, and the nAChR’s genes influence over them is indicative of the exceptional crosstalk that the nicotinic cholinergic receptors share with other systems of the brain.


The CHRNA3, CHRNB4, and CHRNA5, and several other CHRNA and CHRNB genes, have consistently been associated with severity of smoking[15]. CHRNA5 has been associated with a ‘pleasurable buzz’ from early experiences with smoking[16] and, protectively, with cocaine dependence[17]. Cocaine dependence has also been tied to CHRNA5, CHRNA3, CHRNB4[18], and CHRNB3[19]. Similarly, opioid dependence was found to correlate to polymorphisms at CHRNA3[20], CHRNA5, and CHRNB4[21]. Finally, alcohol consumption has been tied to CHRNA3[22][23], CHRNA4[24], CHRNA5, and CHRNA6[25][26], as well as to CHRNB3[27] and CHRNB4[28][29][30]. Separately, binge drinking frequency was found to correlate to polymorphisms at CHRNA4[31].


To continue to the next blog post in this series, click here.

To return to an overview of the blog series on the cholinergic system, click here.

[1] Tournier, J. M., & Birembaut, P. (2011). Nicotinic acetylcholine receptors and predisposition to lung cancer. Current opinion in oncology, 23(1), 83-87. [2] Niu, X. M., & Lu, S. (2014). Acetylcholine receptor pathway in lung cancer: New twists to an old story. World journal of clinical oncology, 5(4), 667. [3] Yoon, K. A., Park, J. H., Han, J., Park, S., Lee, G. K., Han, J. Y., ... & Kubo, M. (2010). A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Human molecular genetics, 19(24), 4948-4954. [4] Young, R. P., & Hopkins, R. J. (2011). How the genetics of lung cancer may overlap with COPD. Respirology, 16(7), 1047-1055. [5] Pillai, S. G., Kong, X., Edwards, L. D., Cho, M. H., Anderson, W. H., Coxson, H. O., ... & Silverman, E. K. (2010). Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine, 182(12), 1498-1505. [6] Boezen, H. M. (2009). Genome-wide association studies: what do they teach us about asthma and chronic obstructive pulmonary disease?. Proceedings of the American Thoracic Society, 6(8), 701-703. [7] Wilk, J. B., Shrine, N. R., Loehr, L. R., Zhao, J. H., Manichaikul, A., Lopez, L. M., ... & Loth, D. W. (2012). Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. American journal of respiratory and critical care medicine, 186(7), 622-632. [8] Hansel, N. N., Ruczinski, I., Rafaels, N., Sin, D. D., Daley, D., Malinina, A., ... & Vergara, C. (2013). Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. Human genetics, 132(1), 79-90. [9] Girard, N., Lou, E., Azzoli, C. G., Reddy, R., Robson, M., Harlan, M., ... & Viale, A. (2010). Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clinical Cancer Research, 16(2), 755-763. [10] Wang, Y., Broderick, P., Matakidou, A., Eisen, T., & Houlston, R. S. (2010). Role of 5p15. 33 (TERT-CLPTM1L), 6p21. 33 and 15q25. 1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis, 31(2), 234-238. [11] Sherva, R., Kranzler, H. R., Yu, Y., Logue, M. W., Poling, J., Arias, A. J., ... & Gelernter, J. (2010). Variation in nicotinic acetylcholine receptor genes is associated with multiple substance dependence phenotypes. Neuropsychopharmacology, 35(9), 1921-1931. [12] Leonard, S., Gault, J., Hopkins, J., Logel, J., Vianzon, R., Short, M., ... & Zerbe, G. (2002). Association of promoter variants in the α7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Archives of general psychiatry, 59(12), 1085-1096. [13] Saur, T., DeMarco, S. E., Ortiz, A., Sliwoski, G. R., Hao, L., Wang, X., ... & Buttner, E. A. (2013). A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target. PLoS genetics, 9(2). [14] Zhao, Y. (2016). The oncogenic functions of nicotinic acetylcholine receptors. Journal of oncology, 2016. [15] Melroy‐Greif, W. E., Stitzel, J. A., & Ehringer, M. A. (2016). Nicotinic acetylcholine receptors: upregulation, age‐related effects and associations with drug use. Genes, Brain and Behavior, 15(1), 89-107. [16] Sherva, R., Wilhelmsen, K., Pomerleau, C. S., Chasse, S. A., Rice, J. P., Snedecor, S. M., ... & Pomerleau, O. F. (2008). Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ‘pleasurable buzz’during early experimentation with smoking. Addiction, 103(9), 1544-1552. [17] Grucza, R. A., Wang, J. C., Stitzel, J. A., Hinrichs, A. L., Saccone, S. F., Saccone, N. L., ... & Fox, L. (2008). A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biological psychiatry, 64(11), 922-929. [18] Sherva, R., Kranzler, H. R., Yu, Y., Logue, M. W., Poling, J., Arias, A. J., ... & Gelernter, J. (2010). Variation in nicotinic acetylcholine receptor genes is associated with multiple substance dependence phenotypes. Neuropsychopharmacology, 35(9), 1921-1931. [19] Haller, G., Kapoor, M., Budde, J., Xuei, X., Edenberg, H., Nurnberger, J., ... & Agrawal, A. (2014). Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence. Human molecular genetics, 23(3), 810-819. [20] Muldoon, P. P., Jackson, K. J., Perez, E., Harenza, J. L., Molas, S., Rais, B., ... & McIntosh, J. M. (2014). The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies. British journal of pharmacology, 171(16), 3845-3857. [21] Erlich, P. M., Hoffman, S. N., Rukstalis, M., Han, J. J., Chu, X., Kao, W. L., ... & Boscarino, J. A. (2010). Nicotinic acetylcholine receptor genes on chromosome 15q25. 1 are associated with nicotine and opioid dependence severity. Human genetics, 128(5), 491-499. [22] Wang, J. C., Grucza, R., Cruchaga, C., Hinrichs, A. L., Bertelsen, S., Budde, J. P., ... & Saccone, S. (2009). Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Molecular psychiatry, 14(5), 501-510. [23] Chen, X., Chen, J., Williamson, V. S., An, S. S., Hettema, J. M., Aggen, S. H., ... & Kendler, K. S. (2009). Variants in nicotinic acetylcholine receptors α5 and α3 increase risks to nicotine dependence. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 150(7), 926-933. [24] Kim, S. A., Kim, J. W., Song, J. Y., Park, S., Lee, H. J., & Chung, J. H. (2004). Association of polymorphisms in nicotinic acetylcholine receptor α4 subunit gene (CHRNA4), μ-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients. Alcohol, 34(2-3), 115-120. [25] Hoft, N. R., Corley, R. P., McQueen, M. B., Huizinga, D., Menard, S., & Ehringer, M. A. (2009). SNPs in CHRNA6 and CHRNB3 are associated with alcohol consumption in a nationally representative sample. Genes, Brain and Behavior, 8(6), 631-637. [26] Landgren, S., Engel, J. A., Andersson, M. E., Gonzalez-Quintela, A., Campos, J., Nilsson, S., ... & Jerlhag, E. (2009). Association of nAChR gene haplotypes with heavy alcohol use and body mass. Brain research, 1305, S72-S79. [27] Haller, G., Kapoor, M., Budde, J., Xuei, X., Edenberg, H., Nurnberger, J., ... & Agrawal, A. (2014). Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence. Human molecular genetics, 23(3), 810-819. [28] Joslyn, G., Brush, G., Robertson, M., Smith, T. L., Kalmijn, J., Schuckit, M., & White, R. L. (2008). Chromosome 15q25. 1 genetic markers associated with level of response to alcohol in humans. Proceedings of the National Academy of Sciences, 105(51), 20368-20373. [29] Broms, U., Wedenoja, J., Largeau, M. R., Korhonen, T., Pitkäniemi, J., Keskitalo-Vuokko, K., ... & Sarin, A. P. (2012). Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits. Nicotine & Tobacco Research, 14(6), 720-733. [30] Hällfors, J., Loukola, A., Pitkäniemi, J., Broms, U., Männistö, S., Salomaa, V., ... & Heath, A. C. (2013). Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study. International journal of molecular epidemiology and genetics, 4(2), 109. [31] Coon, H., Piasecki, T. M., Cook, E. H., Dunn, D., Mermelstein, R. J., Weiss, R. B., & Cannon, D. S. (2014). Association of the CHRNA 4 Neuronal Nicotinic Receptor Subunit Gene with Frequency of Binge Drinking in Young Adults. Alcoholism: Clinical and Experimental Research, 38(4), 930-937.

CONTACT

RESOURCES

SOCIAL

  • YouTube
  • White Instagram Icon
  • Spotify

Blog

©2020 by Leo and Longevity