Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Open accessAbstract
Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by >2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the α5 nicotinic receptor in heavy smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3517–25)
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The second association with nicotine dependence tagged by rs578776 has been replicated in additional studies using the same SNP or a highly correlated SNP.
“This second association with nicotine dependence has been replicated in additional studies using the same SNP or a highly correlated SNP (92,95,96,98).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [95]
The association with rs16969968 has been replicated either directly or using highly correlated SNPs by several groups.
“This association has been replicated either directly or using highly correlated SNPs by several groups (92–97).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [95]
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- Authors
- Stevens, V. L., Bierut, L. J., Talbot, J. T., Wang, J. C., Sun, J., Hinrichs, A. L., Thun, M. J., Goate, A., & Calle, E. E.
- Affiliations
- American Cancer Society (US)
- Washington University in St. Louis (US)
- Corresponding author
- Stevens, Victoria L.
- Venue
- Cancer Epidemiology, Biomarkers & Prevention
- Published
- 2008-12-01
- Volume
- 17
- Issue
- 12
- Pages
- 3517-3525
- ISSN
- 1055-9965 (ISSN-L)
- 1538-7755
- PMC
- PMC2614129
- OpenAlex
- W2134072500
- Cited by
- 190
- References
- 31
- Citations by year
- 2025: 1 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 10 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 11 · 2015: 11 · 2014: 8 · 2013: 19 · 2012: 28
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Epidemiology Biomarkers & Prevention (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alvin J. Siteman Cancer Center
- National Cancer Institute (CA089392, P01CA089392)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- heavy smoking, nicotine dependence, nicotinic acetylcholine receptors, CHRNA5, CHRNA3, CHRNB4, single nucleotide polymorphisms, genetic susceptibility, linkage disequilibrium, non-synonymous mutations, smoking behavior
- MeSH terms
- Aged, Alleles, Female, Genotype, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Prospective Studies, Surveys and Questionnaires, Receptors, Nicotinic, Risk Factors, Tobacco Use Disorder, Genetic Variation, Linkage Disequilibrium, Chi-Square Distribution, Logistic Models, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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