Cholecystokinin (CCK) gene as a possible risk factor for smoking: A replication in two independent samples

Background. CCK is a satiety neuropeptide. Animal studies have shown that both acute and chronic exposure to nicotine results in weight loss which is associated with an increase in hypothalamic CCK and that CCK antagonists ameliorate symptoms of nicotine withdrawal. A major detriment to smoking cessation, especially in women, is the fear of gaining weight. These observations suggested that genetic variants in the CCK gene might be a possible risk factor for smoking. Methods. To test this hypothesis we examined the association of the C-45T promoter polymorphism in the Sp1 binding region of the CCK gene with smoking and BMI in two independent groups of subjects. Results. Group 1 consisted of 191 Caucasian women participating in an obesity study. The T allele was present in 15% of women who had never smoked, 20% of ex-smokers, and 58% of current smokers, P ≤ 0.0014. The T allele was present in 26.8% of ever-smokers (ex-smokers + current smokers). There was no association with BMI. Group 2 consisted of 725 parents of twins from the Minnesota Twin and Family Study of substance abuse. Logistic regression analysis showed that a diagnosis of nicotine dependence was significantly associated with the T allele (P ≤ 0.002) and with gender (males > females) (P ≤ 0.001), but not with BMI (P ≤ 0.68). The T allele was present in 15.9% of parents who had never smoked and 24.7% of ever-smokers, very similar to the results for group 1. Interpretation. These results are consistent with a role of the CCK gene as a risk factor for smoking.