title: Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure.
abstract: BACKGROUND
  Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.
  
  
  METHODS
  We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided.
  
  
  RESULTS
  Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42).
  
  
  CONCLUSIONS
  Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
authors.affiliation: School of Experimental Psychology, University of Bristol, 12a Priory Rd, Bristol BS8 1TU, UK. marcus.munafo@bristol.ac.uk
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafò
authors.forename: Maria N
authors.initials: MN
authors.lastname: Timofeeva
authors.forename: Richard W
authors.initials: RW
authors.lastname: Morris
authors.forename: David
authors.initials: D
authors.lastname: Prieto-Merino
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Johnstone
authors.forename: Caroline
authors.initials: C
authors.lastname: Relton
authors.forename: Paul C D
authors.initials: PC
authors.lastname: Johnson
authors.forename: Donna
authors.initials: D
authors.lastname: Walther
authors.forename: Peter H
authors.initials: PH
authors.lastname: Whincup
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Jefferis
authors.forename: Antoinette
authors.initials: A
authors.lastname: Amuzu
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Mark N
authors.initials: MN
authors.lastname: Upton
authors.forename: Paul
authors.initials: P
authors.lastname: Aveyard
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Graham
authors.initials: G
authors.lastname: Watt
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
mesh_terms: D015415:Biomarkers / Q000097:blood; D002884:Chromosomes, Human, Pair 15; D003367:Cotinine / Q000097:blood*; D005787:Gene Frequency; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*
chemical_list: D015415:Biomarkers; D011978:Receptors, Nicotinic; D003367:Cotinine