A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy

Abstract

Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes. Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some pregnant women continue to smoke. A recent genome-wide association study demonstrated an association between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy, we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds (95% CI 1.11–1.45) of continued smoking during pregnancy (P = 0.0006). Adjustment for pre-pregnancy smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03–1.39); P = 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the first, but not the last, trimester [OR for smoking 10+ cigarettes/day versus 1–9/day in first trimester = 1.30 (95% CI 1.13–1.50); P = 0.0003]. To conclude, we have found strong evidence of association between the rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the previously observed association with smoking quantity. Our data support the role of genetic factors in influencing smoking cessation during pregnancy.

CHRNA3 rs1051730 Genotype and Short-Term Smoking Cessation

“…However, NRT is generally well tolerated at high doses, and in the studies reported here, there was no variation in dose offered. Moreover, this explanation is also not consistent with our failure to observe a differential effect in the placebo and active arms of the Patch II study and the effect of rs1051730 reported in other studies (Baker et al, 2009;Freathy et al, 2009;Thorgeirsson & Stefansson, 2010). A second possibility is that it might be associated with cessation because it influences heaviness of smoking or tobacco dependence.…”

“…While our data on their own are inconclusive with respect to any association between variation in the CHRNA5-A3-B4 gene cluster and short-term smoking cessation in treatment-seeking smokers, it is notable that the magnitude of the effect we observed is consistent with recent evidence from a cohort study of pregnant women (Freathy et al, 2009), a community study of pregnant women (Thorgeirsson & Stefansson, 2010), and a clinical trial of treatment-seeking men and women (Baker et al, 2009). Taken together, these data are suggestive of a weak effect of genetic variation in this region on smoking cessation.…”

“…There may be important differences between this population and the wider population of smokers who attempt to stop smoking, most of whom do so spontaneously and without behavioral or pharmacological support. However, together with previous evidence (Baker et al, 2009;Freathy et al, 2009;Thorgeirsson & Stefansson, 2010), there is now evidence from five independent samples indicating that the rs1051730 variant may be weakly associated with the short-term ability to stop smoking. This may be independent of both heaviness of smoking and tobacco dependence and whether or not the individual is using NRT.…”

“…GWA studies conducted to date, which typically rely on data from retrospective selfreport, have failed to find evidence of association with smoking initiation (comparing ever-and never-smokers) or smoking cessation (comparing current and past smokers). One large cohort study, using prospectively assessed smoking status over the course of pregnancy, showed significant association of the rs1051730 variant with likelihood of smoking cessation, with the risk (T) allele associated with a reduced likelihood of stopping smoking (Freathy et al, 2009). This association remained after adjustment for heaviness of smoking, suggesting that the effect was not mediated solely through heaviness of smoking or tobacco dependence.…”

“…These studies were restricted to pregnant women, some of whom stopped smoking during the course of their pregnancy, assessed either prospectively (Freathy et al, 2009) or retrospectively (Thorgeirsson & Stefansson, 2010). It is unclear, therefore, whether these findings can be generalized to treatment-seeking smokers and whether any association with likelihood of cessation may be modified by the use of pharmacotherapies for smoking cessation, such as NRT.…”