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.

Figure 1

Meta-analysis plots of the association between the rs1051730 variant and BMI, stratified by smoking status. (a) Never/ever smokers. There was strong evidence of heterogeneity between strata (P = 0.0001). In the ever smokers, the effect size equates to a 0.23 kg/m² (95% CI: 0.13−0.31) lower BMI per T-allele. In the never smokers, there was no evidence of association [BMI difference per T-allele: 0.05 kg/m² (95% CI: −0.05 to 0.18)]. (b) Never/former/current smokers. There was strong evidence of heterogeneity among the three strata (P = 0.0002). In the former and current smokers, there was a 0.16 kg/m² (95% CI: 0.03–0.29) and 0.33 kg/m² (95% CI: 0.18–0.48) lower BMI per T-allele, respectively. Overall, across all smoking status strata, each additional T-allele was associated with a 0.10 kg/m² (95% CI: 0.03–0.18) lower BMI