The α5 nAChR subunit is expressed in lung tissue, and a 30-fold upregulation of expression of CHRNA5 mRNA is seen in lung cancer tissue compared with normal lung tissue (41). In addition, tobacco smoke and nicotine can both mediate the stepwise overexpression of nAChR subtypes, which leads to increased Ca2+ permeability in exposed cells (6). Thus, a switch in the nAChR composition (involving the α3 and α5 subunits, among others) could change receptor function, leading to pathologic effects in nicotine-exposed cells. SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster could therefore contribute to increased risk of nicotine dependence and to lung cancer independently and on two levels: (a) by increasing the number of cigarettes smoked and the likelihood of nicotine dependence, and (b) by inserting themselves into the pathophysiological cascade that leads to lung cancer (134).
