The Genetic Determinants of Smoking

doi:10.1378/chest.123.5.1730

Chest

Volume 123, Issue 5, May 2003, Pages 1730-1739

https://doi.org/10.1378/chest.123.5.1730 Get rights and content

Dependence on tobacco, like many other drug dependencies, is a complex behavior with both genetic and environmental factors contributing to the variance. The heritability estimates for smoking in twin studies have ranged from 46 to 84%, indicating a substantial genetic component to smoking. Candidate gene studies have detected functional polymorphisms in genes coding for the cytochrome P450 enzymes, and variations in these genes that lead to more rapid nicotine metabolism have been implicated in smoking. Similarly, smoking has been associated with polymorphisms in dopaminergic genes that may influence the dopamine receptor number and/or function. Animal experiments have localized specific subunits of the nicotinic receptors that may mediate the reinforcing properties of nicotine and have investigated their role in nicotine dependence. However, environmental factors have also been found to contribute to the risk of initiation and persistence of smoking. We review the scientific evidence that supports a role for genetic influences on smoking, discuss the specific genetic and neurobiological mechanisms that may mediate susceptibility to nicotine dependence, identify possible gene/environmental interactions that may be important in understanding smoking behavior, and suggest directions for future research. Insights into the genetic contributions to smoking can potentially lead to more effective strategies to reduce smoking.

Section snippets

Genetic Models

Tobacco smoking is believed to be a complex, multifactorial behavior with both genetic and environmental determinants. The approaches to understand the genetic contributions to smoking include the following: (1) study of individuals who share genes; this includes twin, family, and adoption studies; association studies, case-control studies based on a comparison of unrelated affected and unaffected individuals from a population; an allele A at a gene of interest is said to be associated with the

Twin Studies

The twin pair study has long been a popular research design to investigate genetics in the cause of diseases. Twin studies usually examine concordance rates for traits of interest. If the proportion of monozygotic twins concordant for a given trait is greater than the proportion of dizygotic twins, it is likely that genes influence the trait. If there is no significant difference in concordance rates between monozygotic and dizygotic twins, then the trait is likely to be influenced by

Animal Studies

Since human studies do not permit the manipulation of individual genes and gene products, animal experiments offer the opportunity to systematically examine the biological influence of specific genes on nicotine addiction. Several approaches to the study of animal genetics have been useful in the understanding of nicotine dependence. The most useful include those done with inbred strains, transgenic mice, and knock-out mice.

Genes Influencing Metabolism of Nicotine

There is increasing evidence that tobacco consumption may be influenced by genetically determined variations in the cytochrome P-450 (CYP) group of enzymes, in particular the CYP2A6 enzyme that metabolize nicotine to cotinine³⁴(Fig 1). Along with the normal functional allele CYP2A6*1, two variants of the CYP2A6 gene have been identified: CYP2A6*2 and *3; both are associated with reduced activity of the enzyme. Pianezza et al³⁵ reported that the frequency of individuals with impaired nicotine

Linkage Analysis

Developments in cloning, hybridization, and sequencing techniques have permitted chromosomal localization of several genes influencing neurotransmission. Two studies have suggested evidence for linkage of nicotine addiction to chromosomal regions. Using the Collaborative Study on the Genetics of Alcoholism data, Bergen et al⁸⁶ performed a sibling-pair linkage analysis of two smoking-related traits, ever/never smokers and pack-years. There was some evidence of linkage of the ever/never smoking

Conclusion

Twin and animal studies have consistently found a substantial genetic influence on the development of nicotine dependence. Although definitive evidence is not yet available, variations in several candidate genes may contribute to smoking. Perhaps the most consistent evidence exists for the genes coding for the CYP group of enzymes that lead to increased metabolism of nicotine and the DRD2 genes that regulate dopamine function. However, it is worth noting that environmental factors are also

Future Directions

Most of the genetic data have been obtained from research designs that have limitations in the study of complex behaviors. Also, the inconsistencies in the current body of evidence have limited the clinical utility of the findings. It is increasingly recognized that smokers are not a homogeneous group; moreover, genetic influences on different stages of smoking such as initiation, maintenance, and cessation may not be identical.¹⁹ Researchers may need to examine the behavioral differences

References (92)

JA Dani et al.
Molecular and cellular aspects of nicotine abuse
Neuron
(1996)
AC Heath et al.
Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence
Addict Behav
(1993)
MJ Marks et al.
Genetic influences on nicotine responses
Pharmacol Biochem Behav
(1989)
B Hiremagalur et al.
Nicotine increases expression of tyrosine hydroxylase gene: involvement of protein kinase A-mediated pathway
J Biol Chem
(1993)
R Lovlie et al.
Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene
FEBS Lett
(1996)
EP Noble et al.
D2 dopamine receptor gene and cigarette smoking: a reward gene?
Med Hypotheses
(1994)
DJ Vandenbergh et al.
Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR
Genomics
(1992)
JD Elsworth et al.
Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson’s disease
Exp Neurol
(1997)
RD Todd et al.
Manic-depressive illness and tyrosine hydroxylase markers: Bipolar Disorder Working Group [letter]
Lancet
(1996)
F Thibaut et al.
Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia
Schizophr Res
(1997)

EB Ribeiro et al.

Effects of systemic nicotine on serotonin release in rat brain

Brain Res

(1993)

SJ London et al.

Genetic variation of CYP2A6, smoking, and risk of cancer [letter]

Lancet

(1999)

T Arinami et al.

Polymorphisms in genes involved in neurotransmission in relation to smoking

Eur J Pharmacol

(2000)

GE Swan et al.

The consumption of tobacco, alcohol, and coffee in Caucasian male twins: a multivariate genetic analysis

J Subst Abuse

(1996)

GR Uhl et al.

Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms

Am J Hum Genet

(2001)

R Peto et al.

Mortality from smoking worldwide

Br Med Bull

(1996)

Smoking-attributable mortality and years of potential life lost–United States, 1984

MMWR Morb Mortal Wkly Rep

(1997)

Cigarette smoking among adults–United States, 1997

MMWR Morb Mortal Wkly Rep

(1999)

Cigarette smoking among adults–United States, 1999

MMWR Morb Mortal Wkly Rep

(2001)

RA Fisher

Lung cancer and cigarettes [letter]

Nature

(1958)

RA Fisher

Cancer and smoking [letter]

Nature

(1958)

GF Todd et al.

Concordance of smoking habits in monozygotic and dizygotic twins

Hereditary

(1859)

E Raaschou-Nielsen

Smoking habits in twins

Dan Med Bull

(1960)

JS Williams et al.

Genetic and environmental variance fractions and correlation estimates for smoking behavior in a Swedish population

LJ Eaves et al.

New approaches to the analysis of twin data and their application to smoking behavior

J Kaprio et al.

Cigarette smoking and alcohol use in Finland and Sweden: a cross-national twin study

Int J Epidemiol

(1982)

D Carmelli et al.

Heritability of substance use in the NAS-NRC Twin Registry

Acta Genet Med Gemellol (Roma)

(1990)

D Carmelli et al.

Genetic influence on smoking: a study of male twins

N Engl J Med

(1992)

KL Edwards et al.

Evidence for genetic influences on smoking in adult women twins

Clin Genet

(1995)

MC Hannah et al.

Twin concordance for a binary trait: II; Nested analysis of ever-smoking and ex-smoking traits and unnested analysis of a “committed-smoking” trait

Am J Hum Genet

(1985)

PF Sullivan et al.

The genetic epidemiology of smoking

Nicotine Tob Res

(1999)

KS Kendler et al.

A population-based twin study in women of smoking initiation and nicotine dependence

Psychol Med

(1999)

WR True et al.

Genetic and environmental contributions to smoking

Addiction

(1997)

KS Kendler et al.

Tobacco consumption in Swedish twins reared apart and reared together

Arch Gen Psychiatry

(2001)

RR Fabsitz et al.

A twin analysis of dietary intake: evidence for a need to control for possible environmental differences in monozygotic and dizygotic twins

Behav Genet

(1978)

MA Austin et al.

Risk factors for coronary heart disease in adult female twins: genetic heritability and shared environmental influences

Am J Epidemiol

(1987)

CF Morrison et al.

A comparison of the effects of nicotine and physostigmine on a measure of activity in the rat

Psychopharmacologia

(1968)

PC Hatchell et al.

The influence of genotype and sex on behavioral sensitivity to nicotine in mice

Psychopharmacology (Berl)

(1980)

SF Robinson et al.

Inbred mouse strains vary in oral self-selection of nicotine

Psychopharmacology (Berl)

(1996)

MJ Marks et al.

Characterization of nicotine binding in mouse brain and comparison with the binding of α-bungarotoxin and quinuclidinyl benzilate

Mol Pharmacol

(1982)

LL Miner et al.

Classical genetic analysis of nicotine-induced seizures and nicotinic receptors

J Pharmacol Exp Ther

(1984)

MR Picciotto et al.

Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine

Nature

(1998)

A Orr-Urtreger et al.

Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents

J Neurosci

(1997)

T Nabeshima et al.

Effects of subacute administration of methamphetamine and nicotine on locomotor activity in transgenic mice expressing the human tyrosine hydroxylase gene

J Neural Transm Gen Sect

(1994)

ES Messina et al.

A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes

J Pharmacol Exp Ther

(1997)

ML Pianezza et al.

Nicotine metabolism defect reduces smoking [letter]

Nature

(1998)

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Corroborating evidence for the correlation between the MTHFR C677T single nucleotide variant and smoking in Croatian subjects independent of ischemic stroke
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Hyperhomocysteinaemia is a risk factor for ischemic stroke development. Single nucleotide variation in the methylenetetrahydrofolate reductase gene (MTHFR, C677T polymorphism, T allele) causes a Ala222Val mutation that is associated with hyperhomocysteinemia, cardiovascular disease and stroke. The homozygous TT genotype of MTHFR may also be linked to tobacco smoking in patients from distinct demographic groups. This study evaluated the association of T allele with smoking in a cohort of 301 Croatian adults, including 187 healthy controls and 114 patients with ischemic stroke (IS) and proven ischemic cerebral infarction based on Computed Tomography (CT). Exclusion criteria were hemorrhagic cerebral infarction on CT scan, medical history of diabetes mellitus, and age (>60 years). Cholesterol, triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and C-reactive protein (CRP) were biochemically analyzed. A positive correlation between the TT genotype of MTHFR and smoking was observed within our entire study cohort (p = 0.011). In the control group, the relative frequency of the TT genotype in smokers is complemented by the prevalence of the CC genotype among non-smokers. Hence, our study with Croatian subjects corroborates previous studies indicating that the TT MTHFR variant is linked to smoking. This positive correlation between the TT genotype and smoking represents a confounding parameter that must be accounted for to permit evaluation of statistical associations with stroke and biochemical markers in blood and single nucleotide variations in the MTHFR gene.
Assessment of anxiety, depression and nicotine dependence among construction workers in Chennai - A cross sectional study
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Citation Excerpt :
In Spite of all the efforts the major cause of increase in tobacco users is their dependence on nicotine which is present in tobacco.6 Usually smoking always has a deep connection with their lifestyle and social factors.7 To be precise it also has a relationship with their job stress, anxiety and depression.
Tobacco dependence has been identified as one of the important public health problems faced by both developing and also the developed countries. Anxiety and depression might also influence the quality of life of the tobacco users which increases the dependence on nicotine.
The study was conducted among male construction workers with the habit of tobacco (production workers and labourers) in Chennai who were all working under different organizations from June 15, 2021 to August 15, 2021(n = 416). GAD-7 anxiety severity questionnaire, Patient Health Questionnaire-9, Fagerstrom test for nicotine dependence was used to collect the data. Statistical analysis was done using Statistical Package for the Social Sciences Version 23.
Since the data is normally distributed, Parametric tests have been carried out. A highly statistically significant difference (p = 0.00) was found on finding the association of fagerstrom nicotine dependence with the groups (smokers, smokeless and both users) from One-way ANOVA test. A positive correlation was found between nicotine dependence, GAD-7(r = 0.82) and PHQ-9(r = 0.79).
Nicotine dependence plays a vital role in an individual's anxiety and depression level. Higher the nicotine dependence higher their anxiety and depression level. Long working hours also plays an evident role which influences workers mental health directly.
Illegal tobacco demand: The case of Western Balkan
2020, Economic Analysis and Policy
This paper investigates tobacco smuggling in the Western Balkans, a region notorious as the main smuggling route for Western European countries. Data from a large-scale nationally representative survey from seven Western Balkan countries are used to explore smoking habits, attitudes about the illicit market, and characteristics of smokers associated with illicit market demand. Our results show that, while there are substantial differences between countries in the prevalence of illicit market purchases, the attitudes of people across countries are not dissimilar. The logit model is estimated to analyse the characteristics of illicit market buyers. The results show that purchasing on the illicit market can best be predicted by variables approximating people’s social status. People with lower income and higher levels of addiction are more likely to buy illegal tobacco.
Blowing up money? The earnings penalty of smoking in the 1970s and the 21st century
2018, Journal of Health Economics
We analyze the earnings penalty of smoking among Swedish twins in two social contexts: the 1970s, when smoking was common and widely accepted and when there were relatively few tobacco laws aiming to reduce smoking; and the 2000s, when smoking had become more expensive, stigmatizing and less common, and when tobacco laws and regulations had intensified. The results show that the short-term earnings penalty of smoking was much higher in the 21st century than in the 1970s for men. For women, smokers had on average higher annual earnings compared to nonsmokers in the 1970s, but lower annual earnings in the 2000s. In the long run, there was an earnings gap for men between never-smokers and continuous smokers, whereas there was a pronounced earnings ‘bonus’ of smoking cessation for women. The results emphasize the importance of social context and the long-term horizon when evaluating the consequences of smoking for earnings.
A Clinical Overview of Nicotine Dependence and Withdrawal
2017, Negative Affective States and Cognitive Impairments in Nicotine Dependence
Nicotine dependence is a construct used to classify a cluster of symptoms and behaviors, a syndrome. It is typically associated with heavy consumption of tobacco products, compulsive use, tolerance, regulation of intake, and withdrawal. Nicotine withdrawal and its associated symptoms, which emerge when nicotine consumption is reduced or ceased (ie, during a quit attempt), are typically regarded by smokers as the greatest barrier to quitting. Indeed, nicotine dependence, nicotine withdrawal, as well as the finding that most smokers attempting to quit fail to do so demand further understanding to enable improved treatment approaches and outcomes. This chapter provides an overview of how nicotine dependence develops, its clinical manifestations, the multifaceted nature of withdrawal, and the influential role of negative affect.
α-4 subunit of nicotinic acetylcholine receptor polymorphisms exhibit no association with smoking behavior among Malay Males in Kelantan, Malaysia
2016, Egyptian Journal of Medical Human Genetics
Smoking behavior is influenced by both genetic and environmental factors. Nicotine is the major addictive substance in cigarettes. Nicotinic acetylcholine receptors (nAChRs) are thought to play an important role in nicotine addiction of smokers. One of the genes, α-4 subunit of nicotinic acetylcholine receptor (CHRNA4) gene was reported to be associated with smoking behavior in many populations.
The aim of this study is to determine association between α-4 subunit of nicotinic acetylcholine receptor single nucleotide polymorphism (rs2236196 and rs2273502 loci) and smoking behavior among Malay Males.
The study was conducted in Malay smokers (n = 248) and non-smoking controls (n = 248). DNA was extracted from leucocytes and the two SNPs were determined by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The PCR product was digested with restriction enzymes AfeI and Sau96I, respectively.
We found that the AA genotype frequency for CHRNA4 rs2236196 polymorphism in the smoker group was 80.6% while in nonsmoker 77.0%. No mutation (GG genotype) was detected in both groups. The AG genotype for the smoker group was 19.4% while in the nonsmoker group 23.0%. There was no significant difference observed in the genotype (χ² = 5.106, p = 0.078) and allele frequencies between both study groups. On the other hand, no mutation of CHRNA4 rs2273502 (TT genotype) was detected in the non-smoker group while the frequencies of genotype CC and heterozygous CT in non-smokers were 75.8% and 24.2%, respectively. In the smoker group, the frequencies were 73.4%, 2.0% and 24.6%, for TT, CC and CT, respectively. There was no significant difference observed in rs2273502 (χ² = 5.16, p = 0.078) and smoking behavior of the subjects. In conclusion, the results revealed that CHRNA4 rs2273502 and rs2236196 gene polymorphisms are not statistically significantly associated with smoking behavior in our population.

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Impact of Basic Research on Tomorrow's MedicineThe Genetic Determinants of Smoking

Section snippets

Genetic Models

Twin Studies

Animal Studies

Genes Influencing Metabolism of Nicotine

Linkage Analysis

Conclusion

Future Directions

Neuron

Addict Behav

Pharmacol Biochem Behav

J Biol Chem

FEBS Lett

Med Hypotheses

Genomics

Exp Neurol

Lancet

Schizophr Res

Brain Res

Lancet

Eur J Pharmacol

J Subst Abuse

Am J Hum Genet

Mortality from smoking worldwide

Br Med Bull

Smoking-attributable mortality and years of potential life lost–United States, 1984

MMWR Morb Mortal Wkly Rep

Cigarette smoking among adults–United States, 1997

MMWR Morb Mortal Wkly Rep

Cigarette smoking among adults–United States, 1999

MMWR Morb Mortal Wkly Rep

Lung cancer and cigarettes [letter]

Nature

Cancer and smoking [letter]

Nature

Concordance of smoking habits in monozygotic and dizygotic twins

Hereditary

Smoking habits in twins

Dan Med Bull

Genetic and environmental variance fractions and correlation estimates for smoking behavior in a Swedish population

New approaches to the analysis of twin data and their application to smoking behavior

Cigarette smoking and alcohol use in Finland and Sweden: a cross-national twin study

Int J Epidemiol

Heritability of substance use in the NAS-NRC Twin Registry

Acta Genet Med Gemellol (Roma)

Genetic influence on smoking: a study of male twins

N Engl J Med

Evidence for genetic influences on smoking in adult women twins

Clin Genet

Twin concordance for a binary trait: II; Nested analysis of ever-smoking and ex-smoking traits and unnested analysis of a “committed-smoking” trait

Am J Hum Genet

The genetic epidemiology of smoking

Nicotine Tob Res

A population-based twin study in women of smoking initiation and nicotine dependence

Psychol Med

Genetic and environmental contributions to smoking

Addiction

Tobacco consumption in Swedish twins reared apart and reared together

Arch Gen Psychiatry

A twin analysis of dietary intake: evidence for a need to control for possible environmental differences in monozygotic and dizygotic twins

Behav Genet

Risk factors for coronary heart disease in adult female twins: genetic heritability and shared environmental influences

Am J Epidemiol

A comparison of the effects of nicotine and physostigmine on a measure of activity in the rat

Psychopharmacologia

The influence of genotype and sex on behavioral sensitivity to nicotine in mice

Psychopharmacology (Berl)

Inbred mouse strains vary in oral self-selection of nicotine

Psychopharmacology (Berl)

Characterization of nicotine binding in mouse brain and comparison with the binding of α-bungarotoxin and quinuclidinyl benzilate

Mol Pharmacol

Classical genetic analysis of nicotine-induced seizures and nicotinic receptors

J Pharmacol Exp Ther

Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine

Nature

Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents

J Neurosci

Effects of subacute administration of methamphetamine and nicotine on locomotor activity in transgenic mice expressing the human tyrosine hydroxylase gene

Impact of Basic Research on Tomorrow's Medicine
The Genetic Determinants of Smoking