title: A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.
abstract: 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.
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon 69008, France.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.forename: Valerie
authors.initials: V
authors.lastname: Gaborieau
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Mia
authors.initials: M
authors.lastname: Hashibe
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Anush
authors.initials: A
authors.lastname: Mukeria
authors.forename: Neonilia
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Peter
authors.initials: P
authors.lastname: Rudnai
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fabianova
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.forename: Gary
authors.initials: G
authors.lastname: Goodman
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
authors.forename: George
authors.initials: G
authors.lastname: Xinarianos
authors.forename: Adrian
authors.initials: A
authors.lastname: Cassidy
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Narod
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.forename: Maiken Bratt
authors.initials: MB
authors.lastname: Elvestad
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.forename: Lars
authors.initials: L
authors.lastname: Vatten
authors.forename: Jakob
authors.initials: J
authors.lastname: Linseisen
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Carmen
authors.initials: C
authors.lastname: Martinez
authors.forename: Sheila
authors.initials: S
authors.lastname: Bingham
authors.forename: Torgny
authors.initials: T
authors.lastname: Rasmuson
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Ahrens
authors.forename: Simone
authors.initials: S
authors.lastname: Benhamou
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcátová
authors.forename: Franco
authors.initials: F
authors.lastname: Merletti
authors.forename: Kristina
authors.initials: K
authors.lastname: Kjaerheim
authors.forename: Antonio
authors.initials: A
authors.lastname: Agudo
authors.forename: Gary
authors.initials: G
authors.lastname: Macfarlane
authors.forename: Renato
authors.initials: R
authors.lastname: Talamini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Simonato
authors.forename: Ray
authors.initials: R
authors.lastname: Lowry
authors.forename: David I
authors.initials: DI
authors.lastname: Conway
authors.forename: Ariana
authors.initials: A
authors.lastname: Znaor
authors.forename: Claire
authors.initials: C
authors.lastname: Healy
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.forename: Marc
authors.initials: M
authors.lastname: Delepine
authors.forename: Mario
authors.initials: M
authors.lastname: Foglio
authors.forename: Doris
authors.initials: D
authors.lastname: Lechner
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Helene
authors.initials: H
authors.lastname: Blanche
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
mesh_terms: D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005060:Europe; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: D021122:Protein Subunits; D011978:Receptors, Nicotinic