Multiple studies have confirmed the role of cerebellum in auditory function20, 21, nicotinic cholinergic receptors are present in this brain region35, and hearing loss is one known symptom of cerebellar stroke syndromes36. On these bases, our PheWAS results can be explained by the following hypothesis: smokers with rs113288603 * T have increased CYP2A6 expression in cerebellum that results with consequent altered brain exposure to nicotine and some of its metabolites, and thus protects these subjects from the nicotine-induced changes associated with age-related hearing loss. Specifically, the association of CYP2A6 rs113288603 with age-related hearing loss observed in nicotine-exposed individuals is mediated by the involvement of CYP2A6 in nicotine metabolism (not by the limited effect on smoking quantity observed). This, apparently, has the effect of reducing the long term effects of nicotine on brain regions involved in hearing function. The protein product of CYP2A6 has many other physiological roles, however, our observation ties the effect on hearing directly to exposure to nicotine. This finding contributes to the literature regarding the many toxic effects of nicotine on the human body. Beyond its addictive effects, nicotine can alter important physiological functions, and potentially increase risk for several pathological conditions13, 14.
