Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index

Rachel M Freathy, Gbenga R Kazeem, Richard W Morris, Paul C D Johnson, Lavinia Paternoster, Shah Ebrahim, Andrew T Hattersley, Anita Hill, Aroon D Hingorani, Claus Holst, Barbara J Jefferis, Sofia I I Kring, Vincent Mooser, Sandosh Padmanabhan, Martin Preisig, Susan M Ring, Naveed Sattar, Mark N Upton, Peter Vollenweider, Gerard WaeberThorkild Sorensen, Timothy M Frayling, Graham Watt, Debbie A Lawlor, Peter H Whincup, Federica Tozzi, George Davey Smith, Marcus Munafò

Research output: Contribution to journalArticle (Academic Journal)peer-review

90 Citations (Scopus)


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.

Translated title of the contributionGenetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index
Original languageEnglish
Pages (from-to)1617 - 1628
Number of pages12
JournalInternational Journal of Epidemiology
Issue number6
Publication statusPublished - Dec 2011

Structured keywords

  • Brain and Behaviour
  • Tobacco and Alcohol


  • Adult
  • Aged
  • Body Composition
  • Body Mass Index
  • Clinical Trials as Topic
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins
  • Polymorphism, Single Nucleotide
  • Receptors, Nicotinic
  • Smoking
  • Weight Gain


Dive into the research topics of 'Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index'. Together they form a unique fingerprint.

Cite this