A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
Open accessAbstract
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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Genetic variability in CHRNA5 is a major risk factor for lung cancer and COPD in smokers, likely reflecting higher tobacco dependence and greater exposure to carcinogens and toxins.
“In addition, the same genetic variability in CHRNA5 is also a major risk factor for lung cancer and chronic obstructive pulmonary disease (COPD) in smokers (Amos et al. 2008;Hung et al. 2008;Wang et al. 2010), likely reflecting higher levels of tobacco dependence in individuals carrying risk alleles and consequently greater exposure to carcinogens and”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Hung et al. 2008
The main text identifies a CHRNA5 variant among the markers most strongly associated with lung cancer, including in smokers. Our copy does not report a COPD association. The Supplementary Discussion says the authors found no association with their nicotine-dependence measures and considered tobacco addiction an unlikely explanation for the lung-cancer association, contrary to the proposed mechanism. (LLM, conf=0.90)
Experimental — accuracy not yet measuredOther reports indicate an increased risk of lung cancer even in nonsmokers, suggesting the possibility of a direct effect on lung cancer vulnerability.
“while others report an increased risk of lung cancer even in nonsmokers, suggesting the possibility of a direct effect on lung cancer vulnerability (101,104).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [101]
The replicated nicotine dependence loci tagged by rs16969968 and rs578776 have also been reported to influence lung cancer risk in several genome-wide association studies.
“The replicated nicotine dependence loci tagged by rs16969968 (96,100–102) and rs578776 (101,103) have also been reported to influence lung cancer risk in several genome-wide association studies.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [101]
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- Authors
- Hung, R. J., McKay, J. D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chen, C., Goodman, G., Field, J. K., Liloglou, T., Xinarianos, G., Cassidy, A., McLaughlin, J., Liu, G., Narod, S., Krokan, H. E., Skorpen, F., Elvestad, M. B., Hveem, K., Vatten, L., Linseisen, J., Clavel-Chapelon, F., Vineis, P., Bueno-de-Mesquita, H. B., Lund, E., Martinez, C., Bingham, S., Rasmuson, T., Hainaut, P., Riboli, E., Ahrens, W., Benhamou, S., Lagiou, P., Trichopoulos, D., Holcátová, I., Merletti, F., Kjaerheim, K., Agudo, A., Macfarlane, G., Talamini, R., Simonato, L., Lowry, R., Conway, D. I., Znaor, A., Healy, C., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Matsuda, F., Blanche, H., Gut, I., Heath, S., Lathrop, M., & Brennan, P.
- Affiliations
- Centre international de recherche sur le cancer (FR)
- Russian Cancer Research Center NN Blokhin (RU)
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- Fred Hutch Cancer Center (US)
- University of Liverpool (GB)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Princess Margaret Cancer Centre (CA)
- Women’s College Hospital Research and Innovation Institute (CA)
- Norwegian University of Science and Technology (NO)
- German Cancer Research Center (DE)
- Institute for Scientific Interchange (IT)
- National Institute for Public Health and the Environment (NL)
- UiT The Arctic University of Norway (NO)
- University of Cambridge (GB)
- Umeå University (SE)
- Leibniz Institute for Prevention Research and Epidemiology - BIPS (DE)
- Centre National de la Recherche Scientifique (FR)
- National and Kapodistrian University of Athens (GR)
- University of Turin (IT)
- Institut Català d'Oncologia (ES)
- University of Aberdeen (GB)
- Centro di Riferimento Oncologico (IT)
- University of Padua (IT)
- Newcastle University (GB)
- University of Glasgow (GB)
- Hrvatski zavod za javno zdravstvo (HR)
- Trinity College Dublin (IE)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Fondation Jean Dausset-CEPH (FR)
- Corresponding author
- Brennan, Paul
- ORCID
- Hung, Rayjean J.
- McKay, James D.
- Boffetta, Paolo
- Hashibe, Mia
- Zaridze, David
- Lissowska, Jolanta
- Chen, Chu
- Goodman, Gary
- Field, John K.
- Liloglou, Triantafillos
- Xinarianos, George
- McLaughlin, John
- Liu, Geoffrey
- Narod, Steven
- Skorpen, Frank
- Hveem, Kristian
- Vatten, Lars
- Linseisen, Jakob
- Vineis, Paolo
- Lund, Eiliv
- Hainaut, Pierre
- Ahrens, Wolfgang
- Benhamou, Simone
- Holcátová, Ivana
- Merletti, Franco
- Agudo, Antonio
- Macfarlane, Gary
- Simonato, Lorenzo
- Conway, David I.
- Healy, Claire
- Boland, Anne
- Matsuda, Fumihiko
- Gut, Ivo
- Heath, Simon
- Lathrop, Mark
- Brennan, Paul
- Venue
- Nature
- Published
- 2008-04
- Volume
- 452
- Issue
- 7187
- Pages
- 633-637
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2120240963
- Cited by
- 1,275
- References
- 24
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 22 · 2023: 42 · 2022: 34 · 2021: 28 · 2020: 37 · 2019: 45 · 2018: 42 · 2017: 61 · 2016: 60 · 2015: 83 · 2014: 83 · 2013: 92 · 2012: 130
- FWCI
- 91.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Edge Hill University Research Information Repository (Edge Hill University) (submittedVersion)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Ontario Institute for Cancer Research
- Institut National Du Cancer
- Medical Research Council
- National Cancer Institute (R01CA092039)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- lung cancer susceptibility, nicotinic acetylcholine receptors, CHRNA5, CHRNA3, CHRNB4, chromosome 15q25, single nucleotide polymorphisms, non-synonymous variants, smoking status, peripheral arterial disease, genetic risk factors, alveolar epithelial cells, N'-nitrosonornicotine, therapeutic target, genome-wide association study
- MeSH terms
- Chromosomes, Human, Pair 15, Europe, Genotype, Humans, Lung Neoplasms, Receptors, Nicotinic, Odds Ratio, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Protein Subunits
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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