Occasional smoking might eventually end in addiction. Currently, about 19% of adults around the world smoke tobacco. But, according to the WHO report, there is a global decline in tobacco use, especially among males. In India, according to the Global Adult Tobacco Survey (GATS) (2009-2010) and Global Adult Tobacco Survey (2016-2017) it has shown that there is a 3.3% decline in smoking rates (Fig 1). The global death rates have also declined from 146 per 100,000 people in 1990 to 90 per 100,000 in 2017.
But have you ever wondered why certain people smoke and rest don’t? Addiction and susceptibility to smoking and tobacco intake, cessation and withdrawal symptoms are heritable and are associated with certain genes and genetic polymorphisms. The presence of certain genes leads to an increased risk of developing dependency and addiction towards smoking. This can be understood from the disparity in smoking prevalence and smoking behavior among various races and ethnic groups (Fig 2). There are genetic differences among populations, races, genders and even at an individual level. These differences can be attributed to the different smoking and cessation behavior.
Genetic factors associated with smoking
The various environmental factors like demography, socioeconomic factors and peer pressure associated with smoking and tobacco consumption have been examined previously. But, there are some differences within individuals belonging to the same environment. It is rightly said that, “Genes load the gun. But lifestyle pulls the trigger.” Genomics implementation of research is increasingly being conducted in behavioral medicine. Cigarette smoking and nicotine use disorder, represents a prime area for genomics implementation efforts in behavioral medicine. Individuals without any smoking genes do not feel the urge to initiate smoking or face difficulty in quitting. The presence of smoking genes makes a person inclined towards smoking. These individuals adapt the habit of smoking at the slightest environmental instigation.
Nicotine is the major component of tobacco that causes addiction. Studies showed that smoking initiation is influenced by both genetic and environmental factors. But, once initiated, it’s the genes that decide the number and quantity smoked and the level of dependency. Age of initiation and smoking behavior are influenced by genes. Studies revealed that several genes cause an individual to become more susceptible to being addicted to nicotine. PITRM1 and DHRS7 for African-American smokers and DDR2 for European-American smokers are new candidate genes for smoking initiation and are being studied thoroughly. These genes represent genetic influence on smoking initiation, an important but less studied phenotype in nicotine dependence research. A study conducted by Institute for Health Metrics and Evaluation in 2021, revealed that the age of initiation of smoking differs among various populations (Fig 3).
Nicotine dependence is associated with a single nucleotide polymorphism in DMT3 gene. The polymorphism can occur in the fetal stage or in the adult stage. This polymorphism is found in both heavy and mild smokers. The gene is also associated with smoking induced lung cancer.
The number of cigarettes smoked per day varies for every individual. It has been found that smokers carrying a homozygous CHRNA mutated gene, smoke significantly more tobacco than non-carriers.
The pattern of smoking and smoking behavior is drastically different among individuals. African-American smokers, on average, consume fewer cigarettes daily, inhale more deeply, and break down nicotine more slowly than European-American smokers. This is due to the biochemical differences between the two groups. Genome-wide analyses conducted from 2006 to 2018 showed that the genetic differences on chromosomes 4, 10, 13 and 19 between the two groups are the reason for disparity in smoking patterns and nicotine metabolism.
Various psychological disorders like depression are found to be genetically associated with smoking. It has also been established that there is a genetic association between smoking and BMI. The genetic predisposition for consumption of cigarettes appears to be linked to the genetic predisposition of higher BMI or obesity. It is known that a habitual or an occasional smoker craves for smoking in response to certain environmental stimuli such as stress. Individuals carrying DRD2 (D2 dopamine receptor gene) A1, or the SLC6A3 (dopamine transporter gene) genes have reported to experience a significantly stronger stress induced craving. A person harboring both these genes has an irresistible craving for smoking when in stress.
Gender also plays a major role in the differences in smoking behavior. Smoking activates men’s reward pathways more than women’s. These are due to genetic differences between male and female nicotine receptor genes. The choice of tobacco products, cigarette types are gender biased. These differences in choices are due to gender specific psychological, hormonal and behavioral genes.
Genetic disparity in nicotine metabolism
The pharmacokinetics of nicotine has already been studied elaborately. In the body, nicotine is metabolized to cotinine and trans-3-hydroxycotinine by the enzyme liver cytochrome P450 (CYP). This enzyme is encoded by the gene CYP2A6. Variation in this gene can lead to altered smoking habits. Polymorphisms in CYP2A6 were found in Alaska Native and American Indian (AN/AI) populations but absent in other population groups. This is one of the reasons for the high prevalence of smoking and tobacco in this group. Variations in CYP genes were thoroughly studied in the year 2006, in Indian, Chinese and Malay populations residing in Malaysia. A significant difference has been found in the alleles of these populations (Fig 4).
After inhaling tobacco smoke, nicotine is transported to the brain in ten seconds through the lungs and bloodstream. In the brain nicotine binds to ligand-gated nicotinic cholinergic receptors (nAChRs), which usually binds acetylcholine. This results in the opening of the ion-channel, which allows the entry of Na+ and Ca2+ cations. This, in turn, leads to the activation of voltage-dependent calcium channels, causing an influx of calcium to nerve cells, and, eventually, the release of neurotransmitters. The α4 subunit is a determinant of sensitivity to nicotine. It often exists together with a β2 subunit, which has the strongest nicotine affinity, and some other adjusting subunits. The CHRNA5-CHRNA3-CHRNB4 gene cluster encoding three nicotinic acetylcholine receptor subunits are associated with smoking behaviour. Polymorphisms in these gene clusters result in lower Ca2+ permeability, which reduces nicotine signaling and could thus lead to heavier smoking.
Another gene, SLC6A3 influencing the dopamine pathway is associated with the feel good syndrome of smoking. Mutation or variation in this gene can increase or decrease the desire for smoking based on the type of mutation. A review analysis conducted in the year 2004 showed that the common variants of this gene are a ten-repeat allele found in 70% in European, Caucasian or African-Americans and 90% of Asian or South American populations. The nine-repeat allele is found in 25% in European, Caucasian or African-Americans.
The dopamine receptor gene (DRD) is also associated with smoking behavior. Polymorphisms in DRD genes lead to decreased dopamine receptor expression. Individuals with this polymorphism tend to smoke more to compensate for the reduced dopamine levels.
Monoamine oxidases (MAOs) catalyze deamination of amines, such as dopamine, noradrenaline, and serotonin. This gene is also involved in smoking behavior. Mutation in this gene leading to reduced expressions of the neurotransmitters can cause a person to become a heavy smoker.
Cessation, Withdrawal symptoms and quitting
The neurogenes are responsible for cessation and quitting behavior of individuals. Racial or ethnic differences are also observed in successful quits and smoking relapse. In a particular US based study carried out in 2017, it was observed that Non-Hispanic White adults reported more withdrawal symptoms, withdrawal-related discomfort, and withdrawal-related distress than non-Hispanic Black and Hispanic adults. Certain polymorphisms cause resistance to smoking cessation and no desire to stop smoking. Craving to smoke is a major challenge for those who try to quit smoking. Single nucleotide polymorphisms in Galanin (GAL) and its receptors (GALRs) are associated with severity of craving.
Stress also plays a role in cessation and withdrawal symptoms. Smokers prone to stress have severe withdrawal symptoms and greater risk of smoking relapse. The FKBP5 gene is associated with stress and variations in this gene can affect the severity of withdrawal symptoms and chances of relapse.
The risk of relapse always persists, especially in heavy smokers. It is known to be triggered by environmental stimuli. A genome association study carried out in 2018 showed that a polymorphism in CHRNA5 gene is associated with the risk of nicotine relapse. The mutation is highly present in approximately 35% of Europeans and up to 50% of the population of the Middle East. The relapse is associated with reduced neuronal activation in the interpeduncular nucleus, a brain structure with the highest concentration of α5 nicotinic receptor subunits. Former smokers with increased nicotine receptors are on the higher side of risk for relapse of smoking.
Current treatments and Precision medicine
FDA approved pharmacotherapies and behavioral therapies are used to treat smoking addiction. Medications like varenicline, bupropion and anti-depressants are generally used. But individuals with multi-drug resistant genes or specific neurogenic polymorphisms are not affected by these drugs. The urge to smoke is not reduced by such treatments.
To effectively help a person to let go of smoking behavior, the genotype of the individual must be studied. Smoking must be treated as a genetic disorder and treated accordingly. Varenicline is expected to be more effective in smokers with genotypes associated with reduced dopamine availability. Since nortriptyline has antidepressant properties, like bupropion, nortriptyline is expected to be more effective in smokers with genotypes associated with increased dopamine availability. The genetic influence on withdrawal symptoms are chances for relapse must be analyzed and later for planning a therapy. Likewise, nasal sprays are more beneficial compared to transdermal patches for individuals with reduced expression of nicotine or dopaminergic receptors because of greater rewarding effects of nasal sprays. Individuals with increased expression of μ-opioid receptor (MOR) benefit better with transdermal nicotine patches. It has been found that nicotine replacement therapies do not influence individuals with altered serotonin pathways.
These show that a single therapy cannot be beneficial for all. While treating smoking or nicotine addiction or any addiction at large, each individual is different and should have a specific personalized treatment plan. There has been very limited research on the genetics of the various Indian populations associated with smoking. But, global studies show that smoking patterns are highly influenced by genes. To acquire a tobacco free country, the focus must be transferred deeper to the genetic predisposition of the individuals. The existence of an individual is based on his genes. The various combinations of the four nucleotides determine the appearance, body functioning, behavior, way of thinking, susceptibility to infections, diseases and addiction. With the advancement in technology, the human genotype can be easily analyzed. The genotypes if known, the treatments can be successfully used to eradicate addictions.
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