Due to the relevance of CYP2A6 in nicotine metabolism and the growing literature regarding the potential dangerous consequences of exposure to nicotine from tobacco cigarettes and newer generation tobacco products (e.g., electronic cigarettes)13–15, we conducted a 360-trait PheWAS for nine putative functional CYP2A6 alleles in nicotine-exposed subjects from the Women’s Health Initiative cohort (WHI)16. Our main finding was related to the association of CYP2A6 rs113288603 with hearing loss; there is a known correlation between smoking and age-related hearing loss17, 18. The Women’s Health Initiative cohort includes women in menopause (average age: 61 yrs) and hearing loss in this cohort is considered to be attributable largely to aging processes. This result was replicated in an independent cohort (average age = 69 yrs) from the Long Life Family Study (LLFS)19. We further observed that rs113288603 is associated with CYP2A6 expression in cerebellar hemispheres, which are involved in auditory function20, 21. Our findings confirm the role of tobacco smoking in age-related hearing loss and suggest that CYP2A6 mediates this association (at least in part) by moderating the long-term effects of nicotine or an ototoxic metabolite in the brain to various degrees depending on the individual.
