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/m2 [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/m2 (95% CI: 0.13–0.31) lower BMI (P = 8 × 10−6). The effect size was larger in current [0.33 kg/m2 lower BMI per T-allele (95% CI: 0.18–0.48); P = 6 × 10−5], than in former smokers [0.16 kg/m2 (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.

The importance of gene–environment interactions in human obesity

“…Although there was no evidence of association between variation at rs1051730 and BMI in never smokers, each additional risk allele (T) was associated with a BMI decrease of 0.16 and 0.33 kg/m 2 among former and current smokers respectively [165]. A separate study of 14131 Pakistani adults reported another gene × smoking interaction: the minor allele (T) in FLJ33534 was associated with lower BMI in current smokers and positively associated with BMI among adults who had never smoked [166].…”

“…A meta-analysis of nine European study samples (n = 24198) demonstrated that smoking status moderated the association between genetic variation at the CHRNA5-CHRNA3-CHRNB4 locus (rs1051730) and BMI [165]. Although there was no evidence of association between variation at rs1051730 and BMI in never smokers, each additional risk allele (T) was associated with a BMI decrease of 0.16 and 0.33 kg/m 2 among former and current smokers respectively [165].…”

The causal role of smoking on the risk of hip or knee replacement due to primary osteoarthritis: a Mendelian randomisation analysis of the HUNT study

“…Another potential explanation is the indirect effect of smoking on lifestyle factors such as BMI. Increasing BMI is an established risk factor for OA and subsequent TJR 26,27 and there is evidence to suggest that smoking may lead to lower BMI 18,28,29 , which could mediate the effect of smoking on TJR 30 . However, the association of rs1051730 T alleles with TJR was only slightly attenuated after statistical adjustment for BMI.…”

Does coffee consumption impact on heaviness of smoking?

“…Furthermore, the gene variants with which individuals are born should not be altered by environmental factors, such as the outcome of interest, which removes the issue of reverse causality. This approach has been used to examine the causal impact of cigarette smoking on a variety of health outcomes 5, 6, 7. The identification of genetic variants associated with coffee consumption 8, 9, 10, 11, 12 presents the opportunity to use MR to examine the causal impact of coffee consumption on smoking.…”