title: Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC.
abstract: BACKGROUND
  Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels.
  
  
  METHODS
  We conducted an analysis in a lung cancer case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13.
  
  
  RESULTS
  Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.
  
  
  CONCLUSIONS
  15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation.
  
  
  CONCLUSIONS
  This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Timofeeva
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Mattias
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authors.lastname: Johansson
authors.forename: Graham B
authors.initials: GB
authors.lastname: Byrnes
authors.forename: Amélie
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authors.lastname: Chabrier
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authors.forename: Per Magne
authors.initials: PM
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authors.forename: Stein Emil
authors.initials: SE
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authors.forename: Øivind
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authors.lastname: Midttun
authors.forename: Ottar
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authors.lastname: Slimani
authors.forename: Isabelle
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authors.lastname: Romieu
authors.forename: Françoise
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authors.lastname: Clavel-Chapelon
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.forename: Guy
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authors.lastname: Fagherazzi
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Birgit
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authors.forename: Heiner
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authors.lastname: Boeing
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weikert
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Carla
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authors.lastname: van Gils
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Antonio
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authors.lastname: Agudo
authors.forename: Aurelio
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authors.lastname: Barricarte
authors.forename: Jose-Maria
authors.initials: JM
authors.lastname: Huerta
authors.forename: Laudina
authors.initials: L
authors.lastname: Rodríguez
authors.forename: Maria-José
authors.initials: MJ
authors.lastname: Sánchez
authors.forename: Nerea
authors.initials: N
authors.lastname: Larrañaga
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Nick
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authors.lastname: Wareham
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Allen
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Valentina
authors.initials: V
authors.lastname: Gallo
authors.forename: Teresa
authors.initials: T
authors.lastname: Norat
authors.forename: Vittorio
authors.initials: V
authors.lastname: Krogh
authors.forename: Giovanna
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authors.lastname: Masala
authors.forename: Salvatore
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authors.lastname: Panico
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Torgny
authors.initials: T
authors.lastname: Rasmuson
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Paolo
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authors.lastname: Vineis
authors.forename: Paul
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authors.lastname: Brennan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D015331:Cohort Studies; D003367:Cotinine / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D011978:Receptors, Nicotinic / Q000235:genetics; D012307:Risk Factors; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D003367:Cotinine; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human