Genetic contributions of the α5 nicotinic receptor subunit to smoking behavior

Abstract

Cigarette smoking and tobacco use remain a signifi cant global health problem that kills nearly 6 million people every year [1]. Differences in heaviness of smoking are infl uenced by genetic variation, and compelling evidence from largescale, genome-wide association meta-analyses identifi es the chromosome 15 region, which contains the α5, α3, and β4 nicotinic receptor subunit gene cluster ( CHRNA5, CHRNA3, CHRNB4 ), as the locus that most strongly contributes to heaviness of smoking. Further dissection of this region through human genetic, functional, and animal studies links differences in smoking behaviors to the a5 nicotinic receptor subunit. The same genetic variants in the α5 nicotinic receptor subunit gene that increase the risk of heavy smoking also play a role in failed smoking cessation. Importantly, an interplay exists between these high-risk genetic variants in the α5 nicotinic receptor subunit and pharmacologic treatment so that those at highest genetic risk for failed smoking cessation respond most favorably to pharmacologic treatment to aid cessation. Hopefully this knowledge will improve smoking cessation efforts and reduce the health burdens associated with cigarette smoking.