CYP2A6 Enzyme: The Link Between Nicotine & Genetics

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Source: https://www.nature.com/articles/s41397-020-0147-4

An Improved Assay Shows No Association Between the CYP2A6 Gene and Cigarette Smoking Behavior

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Source: https://link.springer.com/article/10.1023/A:1021642323602

CYP2A6 gene variants may explain smoking status in a Turkish cohort

CYP2A6 Enzyme: The Link Between Nicotine & Genetics

ABSTRACT

OBJECTIVE: Nicotine is the main addictive agent present in tobacco and is principally metabolized by a cytochrome P450-mediated oxidation process.

While smoking patterns differ widely among smokers, the metabolization rate of nicotine can also be affected by variations in rates of enzyme activity between individuals.

Therefore, we aimed to investigate the significance of CYP2A gene variants in the smoking status in a Turkish population using next-generation sequencing (NGS).

METHODS: This case–control study involved 64 subjects with Nicotine dependence (ND) and 36 Non-smoker (NS) subjects. Amplicants designed by “Primer-BLAST” programme were all sequenced using the “Illimuna-MiseqQ-platform”.

RESULTS: It was found that there were five SNPs in the CYP2A6 gene (rs8192725, rs7248240, rs1809810, rs8192733 and rs28399435). CYP2A6 rs1809810 homozygous TT genotype and T allele were seen in lower percentages in ND group compared to the NS group (p =0.

045; p =0.021). Individuals with CYP2A6 rs1809810 TT genotypes and T allele showed odds ratio of 4.760 and 5.360 for developing protective role ND, respectively. CYP2A6 rs8192733 CC genotype and C allele were both lower in ND group (respectively p =0.001, p =0.

023) while GC genotype was higher in the ND group (p =0.004). CYP2A6 rs28399435 TT genotype and T allele were more common in the ND group (respectively p =0.001, p =0.001).

CYP2A6 rs28399435 CC genotype was lower in the ND group than in the NS group (p =0.010).

CONCLUSIONS:CYP2A6 rs1809810, rs8192733, rs28399435 could be genetic risk factors for ND in a Turkish population.

Tobacco use constitutes an important public health problem in addition to its economic burden. Nicotine is the major compound responsible for the development of cigarette addiction.

It leads to addiction by stimulating nicotinic cholinergic receptors (nAChR) that release neurotransmitters into the brain and induce euphoria in the smoker [1]. Nicotine dependence (ND) is regarded as a disease in which genetic factors play a role. These factors include encode proteins in various neurotransmission pathways.

Those that have been suggested as taking a part in the nicotine response include nicotinic cholinergic receptors and nicotine metabolic enzymes [2].

CYP2A6 enzyme is a member of an enzyme superfamily known as the cytochrome P450 system (CYP450), whichis classified in the drug metabolizing enzymes group [1]. These enzymes are located in the endoplasmic reticulum of the cells of several tissues in the body, especially in the liver. CYP2A6 metabolizes up to 70% of nicotine into cotinine through C-oxidation [3].

Several other enzymes of CYP450 such as CYP2B6, CYP2A13, CYP2D6 and CYP2E1 also play a minor role in the nicotine metabolism. The CYP2A6 gene (MIM 122720) was mapped to chromosome 19 where it is found within a 350-bp gene cluster along with the CYP2A7 and CYP2A13 genes [4]. The gene contains 9 exons spanning approximately 6 kb and encodes a protein with 494 amino acids [5].

The most common variants of this gene are single nucleotide polymorphisms (SNPs), which make CYP2A6 highly polymorphic, allowing it to produce isoforms that differ in enzymatic activity; hence, the nicotine level in the body differs from person to person. Smokers with distinct CYP2A6 variants manifest different smoking behaviours from those who do not bear these variants.

This suggests that smokers regulate their nicotine consumption to maintain a certain drug level in the body [6]. CYP2A6 variability has a heterogeneous distribution in populations worldwide, which can explain the various metabolic responses to nicotine that are closely related with ND [1].

Even though some SNPs have been linked with ND in various ethnic populations, they are uncommon in Turkish populations.

Therefore, we conducted a case–control study in a Turkish population to assess the impact of the CYP2A6 gene variants on smoking status in a Turkish population using next-generation sequencing (NGS). The groups were created as ND and non-smoker (NS) groups.

This study is conducted in a single-center, clinic-based, cross-sectional design. We performed a study with a total of 100 individuals enrolled, including 64 smokers (mean age: 47 ± 13) and 36 non-smokers (mean age: 34 ± 12).

All subjects were recruited from the Department of Chest Diseases, Yedikule Hospital for Chest Diseases and Thoracic Surgery Training and Research Hospital in Istanbul, Turkey between January 2015 and February 2016. All subjects were matched for age and sex, and recruited from the same institutions during the same time period.

The ND group consisted of active smokers. These people were defined as those who had previously smoked more than one cigarette/day but had quit smoking for more than one year. The degree of ND was evaluated by the scores on Heaviness of Smoking Index (HSI) and the Fagerström Test for Nicotine Dependence (FTND) [7].

Subjects in the NS group had never smoked in their life. All groups were selected from subjects who had no major medical and chronic diseases. Neither patients nor control subjects suffered from drug or alcohol abuse/dependence. A written informed consent was obtained from each participant.

This study protocol was ap­proved by the Local Ethics Committee (2014/1195) and all the procedures performed in the study were in accordance with the Declaration of Helsinki.

Genomic DNA was isolated from 1.5 mL whole blood collected in EDTA using QIAamp DNA MiniKit (QIAGEN GmbH, Hilden, Germany) and stored at −20°C until analysis. Long range polymerase chain reaction (LD-PCR) was applied for enrichment of CYP2A6 gene.

The primers of amplicants of the CYP2A6 gene were designed by the “Primer-BLAST” programme. Gel electrophoresis was applied to determine the quality and quantity of the purified DNA. DNA samples amplified using Takara LA Taq Polymerase.

Nextera XT DNA Library preparation kit were used for library preparation. DNA library was sequenced on a miSeq instrument with v2 reagent kit (Illumina Inc., San Diego, CA, USA), according to the suppliers’ recommendations.

Variants in the CYP2A6 gene were screened by Illimuna-MiseqQ® -platform. Confirmation of the identified variants was done using the Sanger method.

We used SPSS 13.0 software package (SPSS, Inc., Chicago, ILUSA) for all analyses and calculation. Odds ratios (OR) and 95% confidence intervals (CI) were calculated.

Differences of the CYP2A6 allele and genotype frequencies between groups were assessed using chi-square (χ2) test, with Fisher’s exact test being used when needed.

All analyses were two-tailed, with differences being considered as statistically significant when p value 

Source: https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1547177

Genetic Polymorphism of CYP2A6 and Its Relationship with Nicotine Metabolism in Male Bataknese Smokers Suffered from Lung Cancer in Indonesia

CYP2A6 Enzyme: The Link Between Nicotine & Genetics

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