title: Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.
abstract: A locus at 15q24/15q25.1, which includes the nicotinic acetylcholine receptor A subunits 3 and 5 (CHRNA3 and CHRNA5) genes, has recently been associated with lung cancer risk, self-reported number of cigarettes smoked per day, and a nicotine dependence scale. It is not clear whether the association with lung cancer is direct or mediated through differences in smoking behavior. We used urinary biomarkers to test whether two linked lung cancer risk variants in CHRNA3 (rs1051730) and CHRNA5 (rs16969968) are associated with intensity of smoking and exposure to a tobacco-specific carcinogenic nitrosamine per cigarette dose. We studied 819 smokers and found that carriers of these variants extract a greater amount of nicotine (P = 0.003) and are exposed to a higher internal dose of 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (P = 0.03) per cigarette than noncarriers. Thus, smokers who carry the CHRNA3 and CHRNA5 variants are expected to be at increased risk for lung cancer compared with smokers who do not carry these alleles even if they smoked the same number of cigarettes. Number of cigarettes per day, even if it could be accurately assessed, is not an adequate measure of smoking dose.
authors.affiliation: Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813, USA. oic@crch.hawaii.edu
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Kiersten S
authors.initials: KS
authors.lastname: Derby
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hatsukami
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.forename: Maarit
authors.initials: M
authors.lastname: Tiirikainen
authors.forename: Hansong
authors.initials: H
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009538:Nicotine / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*
chemical_list: D009419:Nerve Tissue Proteins; D009538:Nicotine; D009602:Nitrosamines; D011725:Pyridines; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol