The association between BDNF C270T genetic variants and smoking in patients with mental disorders and in healthy controls
Introduction
Cigarette smoking continues to be one of the most important preventable causes of morbidity and mortality worldwide. Across all risk factors, smoking was the crucial contributor to the mortality differences between men and women in 28 countries (Wu et al., 2021). The harmful effects of smoking are not restricted to smokers, since an involuntary exposure to tobacco smoke is associated with numerous adverse effects in adults, pregnant women, and children (Rojas-Rueda et al., 2021). The relationship between cigarette smoking and severe mental disorders is well-known since smoking might contribute to development of psychiatric disorders, it is associated with brain changes, and might modulate the effects of psychotropic medications (Boksa, 2017). Patients with schizophrenia are three times more likely to smoke (Sagud et al., 2019), and subjects with depression, PTSD, or alcohol abuse or dependence, are two times more likely to smoke (Lasser et al., 2000), than individuals who have no psychiatric disorders. Patients with schizophrenia have lower smoking cessation rates than both healthy controls and subjects with other psychiatric entities (Zeng et al., 2020), and higher prevalence of severe nicotine dependence compared to smokers without psychiatric disease (Sagud et al., 2018a). Individuals with PTSD are generally more dependent and heavier tobacco users than those without a psychiatric condition, but this prevalence is similar to those with other mental health issues (Pericot-Valverde et al., 2018). Psychiatric patients have more severe health consequences of tobacco consumption than individuals without psychiatric disorders, with tobacco use being greater contributor to their mortality than their behavioral disorder (Williams et al., 2013).
Nicotine is the main psychoactive component in tobacco, which binds to nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area and increases dopamine release in the brain reward system. Such positive reinforcing effects are the main source of motivation for cigarette smoking and dependence. Nicotine mediates increase of dopamine via nAChR, but acts also through the glutamate, GABA, and opioid systems (Mackillop et al., 2010). Besides these neurotransmitters involved in the effects of nicotine, brain-derived neurotrophic factor (BDNF) was suggested to be a key molecule for the activation of brain reward system after nicotine exposure (Huang et al., 2020), given its crucial role for the survival and maintenance, as well as excitability and regulation of the dopamine mesolimbic circuits (Douma and de Kloet, 2020). In animal models, nicotine increased BDNF and tyrosine receptor kinase B (Trk B) levels in hippocampus of mice exposed to stress (Khalifeh et al., 2020). Nicotine also increased BDNF release in the striatum, which stimulates BDNF-mediated TrkB signaling cascades in GABAergic neurons, leading to the nicotine-seeking behavior (Kim et al., 2019). Smokers were reported to have higher serum BDNF levels, but, interestingly, serum BDNF levels were similar in nicotine dependent and non-dependent smokers (Jamal et al., 2015a). In general, nicotine upregulated BDNF gene expression by epigenetic modifications, α7 nAChR stimulation, and by increasing the dopamine release (Huang et al., 2020).
The relationship between BDNF and nicotine consumption is bidirectional. While nicotine alters BDNF gene expression, the BDNF gene polymorphisms may impact smoking behavior, i.e. individuals with specific BDNF genetic variants may be more likely to initiate and maintain smoking (Tobacco and Genetics Consortium, 2010; Breetvelt et al., 2012).
Several genetic variants have been identified within the BDNF gene, but the BDNF Val66Met polymorphism (rs6265), resulting in valine (Val) to methionine (Met) substitution, has been the most extensively studied in the genetic association studies of many psychiatric and neurological disorders. This polymorphism was linked to the magnitude of BDNF release, and BDNF Met allele has been associated with the decreased ability of pro-BDNF to be packed from Golgi apparatus into secretory vesicles and released into synapse (Egan et al., 2003). Given the complex link between BDNF signaling and smoking, functional polymorphisms within the BDNF gene may be expected to moderate this relationship. However, the studies addressing BDNF Val66Met polymorphism and smoking have yielded inconsistent findings: positive associations with genome wide association studies (GWAS) (Xu et al., 2020) and the association (Lang et al., 2007) or meta-analyses (Korhonen et al., 2020; Zhao et al., 2020) studies, or negative associations (Montag et al., 2008; Jamal et al., 2015a; Zhang et al., 2012; Ohmoto and Takahashi, 2019; Suriyaprom et al., 2013; Xia et al., 2019) were reported.
Other polymorphisms within the BDNF gene, such as BDNF C270T polymorphism, may also influence brain BDNF signaling, and thus influence the smoking behavior. The BDNF C270T (rs56164415) polymorphism is located on the 5′-non-coding region of BDNF gene, acting as a functional promoter polymorphism (Xu et al., 2017), which may impact the gene expression efficacy (Kunugi et al., 2001). It was reported that the substitution of the C allele with the T allele might contribute to the loss of transcription factors Histone H4 Transcription Factor and ZIC3 (zinc finger protein family member 3) binding sites, which were hypothesized to impair the efficacy of BDNF translation in neurons, producing BDNF imbalances in the cortex (Xu et al., 2017). There are no studies evaluating the BDNF C270T polymorphism and smoking status.
The inconsistencies across studies may be attributed to differences in allele distributions across diverse populations. For example, the frequency of the Met allele of the BDNF Val66Met polymorphism was about 50% in Chinese in contrast to 20% in Caucasian subjects (reviewed in Huang et al., 2020), while the Val allele was represented in 78.4% in Caucasian, but only in about 51.5% of Asian population (Zhao et al., 2020). There was also a significant difference in the frequency of the Met allele between the Korean (46.3%) vs. 19.5% in the Caucasian (from the Croatian origin) healthy subjects (Pivac et al., 2009). Likewise, the higher frequency of the BDNF C270T T alleles was reported in Caucasian than in East Asian population (Watanabe et al., 2013). Such ethnic differences may have contributed to different findings regarding the role of BDNF Val66Met and BDNF C270T genetic variants in smoking behavior in both heathy individuals and psychiatric patients.
To best of our knowledge, no study addressed the association of BDNF Val66Met and C270T polymorphisms with smoking status simultaneously in several samples with distinct psychiatric diagnoses, in Caucasian participants from the same ethnic origin and sampled from the same county (Zagreb county). The hypothesis of the study was that the A allele of the BDNF Val66Met and the T allele of the BDNF C270T polymorphisms will be overrepresented in smokers compared to nonsmokers. Therefore, the present study focused on the association between the BDNF Val66Met and BDNF C270T polymorphisms and smoking status in patients with 1) schizophrenia, 2) alcohol dependence, 3) major depression, 4) PTSD and 5) in healthy individuals, in ethnically homogeneous Caucasian population of the Croatian origin.
Section snippets
Participants
This study included 3502 Caucasian subjects: 2541 male and 960 female subjects, all of the Croatian origin. Out of them there were 918 healthy controls and 2584 patients with mental disorders. Patients were subdivided into 519 individuals with current and chronic PTSD, 419 individuals with a major depressive disorder (referred further as depression), 996 patients with schizophrenia, and 650 patients with alcohol dependence. All subjects were sampled from the university hospitals from the Zagreb
Demographic data of the participants
Patients with schizophrenia were significantly younger (p < 0.001) than healthy controls (p < 0.001), patients with alcohol dependence (p < 0.001), depression (p < 0.001) or with PTSD (p < 0.001). There was a significant difference in the prevalence of smoking between different diagnostic groups (Table 1). Patients with PTSD (R = 4.5), schizophrenia (R = 4.1) and alcohol dependence (R = 3.0) were more frequently smokers than patients with depression (R = 1.8) and healthy control subjects (R
Discussion
Main finding of this study was that the BDNF C270T polymorphism was significantly associated with smoking status in the large, merged groups of Caucasian healthy subjects and patients with different mental disorders, subdivided into smokers and non-smokers. The presence of one or two T allele of the BDNF C270T was more frequently found in smokers than in non-smokers with schizophrenia, PTSD, depression, alcohol dependence and in healthy subjects. These results were confirmed with the regression
Conclusion
This study is the first to report a significant association between BDNF C270T polymorphism and smoking status in large Caucasian cases/controls. However, the number of cigarettes smoked per day was not related to C270T polymorphism. The presence of the T allele of the BDNF C270T polymorphism was associated with smoking in healthy control subjects. In contrast, this study did not confirm a significant association between the BDNF Val66Met polymorphism and smoking, but heaviness of smoking was
Contributors
Nela Pivac developed the original idea and designed the study.
Nela Pivac, Suzana Uzun, Gordana Nedic Erjavec and Matea Nikolac Perkovic realized the experimental parts of the study: clearly explained the research goals and described protocol in details to the patients; explained the importance of strict adherence to the sampling methods and heart rate measurement, and explained the inclusion/exclusion criteria, and emphasized the importance of strict adherence to the protocol.
Suzana Uzun,
Ethical statement
All participants were familiarized with the aims and the procedures of the study. After the careful explanation, they signed the informed consent. The authors affirm that all procedures of the study are in accordance with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human subjects were approved by the Ethics Committees of the University Hospital Center
Declaration of Competing Interest
None.
Acknowledgement
This work was supported by the Croatian-USA collaborative project: The association between stress, genetic variants of the catechol-O-methyltransferase (COMT) and mu opioid receptor gene (OPRM1) polymorphisms and tobacco smoking in patients with schizophrenia; among University of Michigan, USA, Rudjer Boskovic Institute, Croatia and University Psychiatric Hospital Vrapce, Zagreb, Croatia (PIs: Nela Pivac and Edward F Domino).
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Nela Pivac and Gordana Nedic Erjavec: equally contributing authors