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Year : 2022  |  Volume : 25  |  Issue : 2  |  Page : 160-166

Methylation of APC2, NR3C1, and DRD2 gene promoters in turkish patients with tobacco use disorder

1 Department of Chest Disease, University of Health Sciences, Yedikule Training and Research Hospital of Chest Diseases and Thoracic Surgery, Istanbul
2 Department of Chest Disease, University of Health Sciences, Yedikule Training and Research Hospital of Chest Diseases and Thoracic Surgery, Istanbul, Turkey
3 Department of Psychiatry, Malazgirt State Hospital, Mus, Turkey
4 Department of Medical Biology, University of Istanbul, Istanbul, Turkey
5 Department of Chest Disease, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey

Date of Submission15-Jan-2021
Date of Acceptance30-Aug-2021
Date of Web Publication16-Feb-2022

Correspondence Address:
Dr. Cinarka Halit
University of Health Sciences Turkey, Yedikule Training and Research Hospital of Chest Diseases and Thoracic Surgery, Istanbul, 34760

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njcp.njcp_25_21

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Background: Many studies have investigated the association of the methylation of gene and tobacco use disorders (TUD), but results remain ambiguous. Aims: This study evaluated the relationship between methylation of Adenomatosis Polyposis Coli (APC), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Dopamine D2 receptor (DRD2) gene promoters, and its effect on TUD. Subjects and Methods: We recruited 154 active smokers and 111 healthy non-smoker controls. PCR based methods on genomic DNA characterized the methylation of APC2, NR3C1, and DRD2 gene promoters. Results: We have found a significant difference in methylation of APC2 for TUD compared to healthy controls (P < 0.001). The partial methylation ratio was about an eight-fold increase in smokers compared to healthy controls. NR3C1 methylation was slightly higher in TUD patients compared to the control group, but the difference was not significant between the two groups (%95.33 vs. 91.08, P = 0.269). DRD2 methylation ratio was not significant between TUD patients and healthy control groups (P = 0.894). Conclusion: We think that it is important to detect APC2 methylated cases earlier and to advise them to quit smoking.

Keywords: APC2, DRD2, methylation, NR3C1, tobacco

How to cite this article:
Halit C, Elif y N, Hasan M A, Sacide P, Yasemin O, Deniz D, Mehmet A U. Methylation of APC2, NR3C1, and DRD2 gene promoters in turkish patients with tobacco use disorder. Niger J Clin Pract 2022;25:160-6

How to cite this URL:
Halit C, Elif y N, Hasan M A, Sacide P, Yasemin O, Deniz D, Mehmet A U. Methylation of APC2, NR3C1, and DRD2 gene promoters in turkish patients with tobacco use disorder. Niger J Clin Pract [serial online] 2022 [cited 2022 Dec 2];25:160-6. Available from:

   Introduction Top

Tobacco use is a disorder (TUD), which now includes “tobacco addiction” or “nicotine dependence” terms according to DSM-5, responsible for killing more than eight million people a year around the world.[1] TUD can cause pulmonary, cardiovascular, and neoplastic diseases that have been related to at least 17 types of human cancer, leading to high health costs to communities.[2] The exposure to tobacco smoke may induce DNA methylation or the formation of covalent bonds between the carcinogens and DNA, the resulting accumulation of persistent somatic mutations in well-known genes.[2] Nuclear Receptor subfamily 3 group C member 1 (NR3C1) gene consists of eight introns and nine exons on chromosome 5q31-32 encoding the glucocorticoid receptor.[3] Various transcriptional and translational mechanisms regulate expression of the NR3C1. Altered NR3C1 methylation is associated with early stress exposure and thus may cause the occurrence of psychopathology, including alcohol–tobacco consumption.[4] In previous studies, NR3C1 was identified epigenetically in breast cancer[5] and small cell lung cancer[6] that constitutes approximately 15% of all lung cancer samples and tightly associated with TUD.[7] Genetic and environmental risk factors such as air pollution and smoking contribute to lung carcinogenesis.[8] The dopaminergic reward system plays a crucially important role in addiction to tobacco, alcohol, and other abused drugs, as well as non-substance use disorders like pathologic gambling.[9],[10] In addiction behavior, different studies have focused on the role of changes in DNA methylation in these dopaminergic genes such as the dopamine transporter gene and Dopamine D2 receptor (DRD2) gene, which has been widely investigated in the literature. DRD2 methylation alteration is associated with gambling behavior,[10] and Tourette syndrome[11] besides Alcohol Use Disorder (AUD) and TUD.[9] However, dopamine receptors are mainly located in the central nervous system, which has numerous functions in the clinical progression of non-small cell lung cancer (NSCLC) and functional maintenance of cancer cells.[12] About 25–30% of NSCLC are squamous cell carcinoma (SCC), strongly related to a history of having ever smoked.[8] The well-known tumor suppressor gene Adenomatosis Polyposis Coli (APC) has been associated with many malignancies, including colorectal cancer,[13] retinoblastoma,[14] lymphocytic leukemia,[15] ovarian cancer,[16] and NSCLC.[17] Its homolog gene, APC2, is located on chromosome 19p13.3, encoding a protein that controls the stability and nuclear export of β-catenin and regulates the Wnt signaling pathway.[18] As smoking is thought to be included in the early stages of tumorigenesis, tobacco smoking may be related to mutations in the APC gene.[19] Although there were some researches about the relationship between APC2, NR3C1, and DRD2 genes methylations with Substance Use Disorders (SUD) and lung cancer through a variety of mechanisms, there were not enough study that investigated relationship methylation of APC2, NR3C1, and DRD2 gene promoters and its effect on TUD. To our knowledge, prior studies have not specifically targeted the influences of APC2 methylation on the effects of TUD.

We aimed to evaluate the relationship between TUD and the methylation of APC2, NR3C1, and DRD2 gene promoters by comparing the methylation of these genes between TUD patients and healthy controls.

   Subjects and Methods Top

Study population

We performed a case-control study and included subjects with TUD patients (72 females and 82 males; mean age: 43.23 ± 13.01). They were recruited from smoking cessation outpatient clinic and general population in XXXXX and 111 healthy non-smoker controls (64 females and 47 males; mean age: 36.25 ± 13.06). The smoker group consisted of active smokers. These people were defined as those who have smoked more than one cigarette/day Data on the average amount of tobacco consumed per day was recorded for all smokers. The smoking degree was evaluated by the scores on the Fagerstrom Test for Nicotine Dependence (FTND). The Control group was selected from 'Non-smokers' and the subjects included had smoked less than one cigarette per day for no more than 1 year during their lifetime. All patients and control groups were of the same ethnic origin, declared as Turkish ethnicity. Both the study and the control groups contained individuals non-relevant and above 18 years of age.

Sociodemographic and clinical characteristics data form

A detailed interview data form prepared by the researchers was used and included questions were about clinical information such as sociodemographic characteristics and nicotine dependence.

Fagerstrom test for nicotine dependence (FTND)

First proposed in 1978 and developed in 1991, the FTND consists of six questions. It is easily understood and rapidly applied. FTND scores are typically grouped into distinct levels, namely low nicotine dependence (0-3 points), medium nicotine dependence (4-6 points), and high nicotine dependence (≥7 points). A Turkish validation study of the test was performed by Uysal et al.[20] and found FTND to be reliable. Informed consent was obtained from all participants before they enrolled in the study. This study was conducted following the Declaration of Helsinki and was approved by the Ethics Committee of Istanbul University, Faculty of Medicine (Aug 8, 2019, and number: 943).

Laboratory analyses

Blood samples and DNA extraction

From the patients with TUD and the control groups, 10 mL peripheral venous blood samples were collected in ethylenediaminetetraacetic acid tubes. Genomic DNA was extracted from whole blood by using the Plus Blood Genomic DNA Purification test kit (GeneMark). Nanodrop-2000C Spectrophotometer was used for checking concentration and purification of all isolated DNA samples.

Bisulfite modification

After isolation of DNA, bisulfite modification is an accepted gold standard procedure to detect methylation of DNA. We used the EZ-96 DNA Methylation-Gold kit according to manufacturer recommendations (Zymo Research) for this analysis.

Methylation-specific polymerase chain reaction (MSP PCR)

Modified DNA samples were subjected to MSP using NR3C1, DRD2, and APC2 primers [Table 1]. One pair of methylated primers were used to amplify methylated regions and one pair of unmethylated primers to amplify unmethylated regions. Bisulfite converted DNA samples were amplified by PCR with Zymo Taq DNA polymerase (Zymo Research) with the primers at the following conditions: 10 minutes at 950C, 40 cycles (30 seconds at 950C, 40 seconds at annealing temperature for each primer, and 45 seconds at 720C), and 720 C for 7 minutes [Table 1]. The products were separated on 3% agarose gel and visualized under UV light and taken photos [Figure 1],[Figure 2], [Figure 3].
Table 1: Primers and PCR amplification conditions

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Figure 1: NR3C1 gene methylation analysis. PK: Positive control, NK: Negative control, M: Methylated, U: Unmethylated, 2 and 4: partial-methylated, 1 and 3: unmethylated

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Figure 2: DRD2 gene methylation analysis.PK: Positive control, NK: Negative control, M: Methylated, U: Unmethylated, 1 and 2: partial-methylated, 3, 4, and 5: unmethylated

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Figure 3: APC2 gene methylation analysis. PK: Positive control, NK: Negative control, M: Methylated, U: Unmethylated, 1 and 2: partial-methylated, 3, 4, and 5: unmethylated

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Statistical analyses

Statistical analysis was performed using Stata (StataCorp. 2017. Stata Statistical Software: Release 15.2 College Station, TX: StataCorp LLC). Mean and standard deviation was used for the presentation of continuous quantitative variables. Frequencies and percentages were used for categorical data. APC2, NR3C1 Distributions were compared by using Chi-square, Fisher's exact test. For the multivariate analysis, gender, age, and APC2 were entered into a logistic regression analysis to determine independent predictors of TUD. The Hosmer–Lemeshow goodness-of-fit statistics were used to assess model fit. Statistical significance was accepted as P < 0.05.

   Results Top

We compared APC2 methylation, NR3C1 methylation, and DRD2 methylation between TUD patients and healthy controls. We found that partial APC2 methylation was higher in smokers compared to healthy controls. The difference was statistically different (P < 0.001). NR3C1 methylation was slightly higher in TUD patients compared to the control group, but the difference was not significant between the two groups (%95.33 vs. 91.08, P = 0.269). DRD2 methylation ratio was similar between TUD patients and a healthy control group. The difference was not significant between smokers and never healthy controls (P = 0.894) [Table 2]. According to the logistic regression model, the partial methylation ratio was about an eight-fold increase in the TUD group compared to healthy controls (P < 0.001) [Table 3]. APC2, NRC1 methylation, DRD2 methylation, and TUD group's clinical parameters are summarized in [Table 4].
Table 2: TUD patients and control group methylation

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Table 3: The relation between TUD and gender, age, and APC2 methylation

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Table 4: APC2, NRC1 methylation, DRD2 methylation, and TUD group's clinical parameters

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   Discussion Top

To our knowledge, this is the first study that has evaluated the relationship between the methylation of APC2, NR3C1, and DRD2 gene promoters and TUD in the Turkish population. In the present study, we showed that APC2 methylation was higher in TUD than the control group. The partial methylation ratio was about an eight-fold increase in smokers compared to healthy controls. NR3C1methylation was slightly higher in TUD cases compared to the control group, but then there was no significant difference between the two groups. DRD2 methylation ratio was similar between the TUD group and the healthy control group.

Currently, many epigenome-wide association studies (EWASs) have shown that TUD is associated with alterations in DNA methylation, an epigenetic modifier of gene expression.[21] Smoking-related changes in the methylation of CpG sites found in genes such as Aryl-Hydrocarbon Receptor Repressor (AHRR), G-protein coupled receptor 15 (GPR15), and Coagulation Factor II (Thrombin) Receptor-Like 3 (F2RL3) have been published.[22] In patients diagnosed with TUD, the methylation signals mostly show lower levels of DNA methylation compared to healthy controls. These epigenetic events show tissue-specificity and vary by ethnicity, and can serve as markers of long-term exposure to tobacco smoke.[23] In the present study, there was a statistically significant difference between the methylation of the APC2 gene promoter (partial methylation, unmethylation) of the TUD patients and the control group. The frequency of partial methylation APC2 gene was significantly higher in the TUD group in comparison with the control group. In the literature, although APC2 is hypermethylated in malignancies such as colorectal cancer[13] and retinoblastoma,[14] no studies on carcinogens such as cigarette smoke that may affect methylation in the APC2 gene have been found. Barrow et al.[24] published evidence of hypermethylation of the APC1A gene, which implicated in tobacco-related colorectal carcinogenesis, and promoter hypermethylation was positively associated with the duration of TUD. The identification of promoter hypermethylation on Ras Association Domain Family Member 1 (RASSF1A) and APC genes compared with healthy controls was also much more frequent in early-stage lung cancer patients. However, no significant difference was found between APC methylation frequency and tobacco usage in patients.[25] Gao et al. reported 13 tobacco-associated CpG sites within eight genes suggested, being related to lung cancer in their genome-wide association studies (GWAS). They identified smoking-induced hypermethylation for loci within Cholinergic Receptor Nicotinic Alpha 5 Subunit (CHRNA5) and serine/threonine kinase 32B (STK32), and smoking-induced hypomethylation for loci within Actin Alpha 2, Smooth Muscle (ACTA2), GATA Binding Protein 3 (GATA3), Kruppel Like Factor 6 (KLF6), MutS Homolog 5 (MSH5), Telomerase Reverse Transcriptase (TERT), and Vesicle Transport Through Interaction With T-SNAREs 1A (VTI1A)(27).[21] Our study is the first in this field to report the relationship between hypermethylation of APC2 gene promoter and TUD.

In our study, the methylation of NR3C1 gene promoter was not significantly different between TUD patients and healthy control group; even the researches have shown differences in NR3C1 methylation related to major depressive disorder,[26] post-traumatic stress disorder,[27] suicidal behavior,[28] bulimia nervosa,[29] borderline personality disorder,[30] and alcohol-tobacco consumption.[4] Therefore, we speculate that our results suggest that epigenetic aberrations of NR3C1 are not associated with the pathophysiology of TUD in the Turkish population. In the literature, various candidate gene association studies evaluated the function of NR3C1 gene polymorphism in TUD. Rogausch et al.[31] showed that there was an association between NR3C1 rs41423247 polymorphism and TUD severity. G allele was significantly associated with an increased probability of being TUD and higher daily cigarette consumption. Siiskonen et al.[32] investigated the influence of NR3C1 rs41423247 polymorphism on TUD in their follow-up study with a large population cohort sample. They found no significant difference in smoking status or severity between genotype groups. When the main effect of the rs6198 on TUD was evaluated in a population sample by Rovaris et al.,[33] again, no association of NR3C rs6198 with TUD was observed. Dogan et al.[4] investigated the effects of alcohol and cigarette exposure by examining peripheral DNA methylation at NR3C1 and FKBP5 genes. They found that the influence of alcohol and smoke consumption is more noticeable at the FKBP5 gene than the NR3C1 gene, although higher demethylation in both genes was significantly related to increased tobacco and alcohol consumption.

The association of genetic variants in the dopaminergic system with the molecular mechanisms underlying TUD has been deeply evaluated.[34] The rs1800497 polymorphism of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene, which is adjacent to the DRD2 gene, is known to be related to TUD.[35] The A1 allele of ANKK1 gene polymorphism increases the risk of TUD in the Caucasian population,[36] whereas studies with the Japanese population reported an association between the A2/A2 genotype and the risk of TUD.[37] When Lerman et al.[38] investigated the risk of TUD related to the Solute Carrier Family 6 Member 3 (SLC6A3) (dopamine transporter gene) and DRD2 gene polymorphisms in their case-control study, they reported that the SLC6A3 gene polymorphism might influence smoking initiation and occurrence of TUD. When the smoking-related methylation of the Neural Cell Adhesion Molecule 1 (NCAM1)–Tetratricopeptide Repeat Domain 12 (TTC12)–ANKK1–DRD2 cluster was analyzed by Liu et al.[39] in the Chinese Han population, they found that the majority of smoking-related methylation alterations are located in the ANKK1/DRD2 region. Again, Hillemacher et al. published that TUD is independently associated with higher DRD2 gene methylation in patients diagnosed with AUD and healthy controls in the German population. In our study, comparing the methylation of the DRD2 gene promoter between the TUD and healthy control groups, there was no significant difference between the two groups. When the literature is reviewed, apart from the above two studies, there is no research examining the relationship between the methylation of the DRD2 gene promoter and TUD. Our present study is the first in this field to show that there was no association between the methylation of the DRD2 gene promoter and TUD.

Although our study has several limitations, its strength is that it was the first report examining potential associations between Turkish TUD patients and methylation of APC2, NR3C1, and DRD2 gene promoters. The first limitation was the small sample size, which can limit the statistical power. In our study, only DNA methylation was analyzed, whereas other epigenetic mechanisms (i.e., histone modification or miRNA) were not considered.

In conclusion, in our study, while the methylation of the APC2 gene promoter may be related to the TUD, the methylation of NR3C1 and DRD2 gene promoters was not found to be associated with TUD. Confirmation of these findings with other epigenetic mechanisms in different ethnic populations will provide a better understanding of the relationship between these gene methylations and TUD. Patients who are positive for these markers should be followed up in terms of cancer after quitting smoking and will contribute to the literature.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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