title: Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.
abstract: BACKGROUND
  Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers.
  
  
  METHODS
  We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24,198) and then tested for a genotype × smoking status interaction.
  
  
  RESULTS
  There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m(2) [95% confidence interval (95% CI): -0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m(2) (95% CI: 0.13-0.31) lower BMI (P = 8 × 10(-6)). The effect size was larger in current [0.33 kg/m(2) lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 × 10(-5)], than in former smokers [0.16 kg/m(2) (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001).
  
  
  CONCLUSIONS
  Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI.
authors: The MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK.
authors: Rachel M
authors: RM
authors: Freathy
authors: Gbenga R
authors: GR
authors: Kazeem
authors: Richard W
authors: RW
authors: Morris
authors: Paul C D
authors: PC
authors: Johnson
authors: Lavinia
authors: L
authors: Paternoster
authors: Shah
authors: S
authors: Ebrahim
authors: Andrew T
authors: AT
authors: Hattersley
authors: Anita
authors: A
authors: Hill
authors: Aroon D
authors: AD
authors: Hingorani
authors: Claus
authors: C
authors: Holst
authors: Barbara J
authors: BJ
authors: Jefferis
authors: Sofia I I
authors: SI
authors: Kring
authors: Vincent
authors: V
authors: Mooser
authors: Sandosh
authors: S
authors: Padmanabhan
authors: Martin
authors: M
authors: Preisig
authors: Susan M
authors: SM
authors: Ring
authors: Naveed
authors: N
authors: Sattar
authors: Mark N
authors: MN
authors: Upton
authors: Peter
authors: P
authors: Vollenweider
authors: Gerard
authors: G
authors: Waeber
authors: Thorkild I A
authors: TI
authors: Sørensen
authors: Timothy M
authors: TM
authors: Frayling
authors: Graham
authors: G
authors: Watt
authors: Debbie A
authors: DA
authors: Lawlor
authors: Peter H
authors: PH
authors: Whincup
authors: Federica
authors: F
authors: Tozzi
authors: George
authors: G
authors: Davey Smith
authors: Marcus
authors: M
authors: Munafò
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