Genetic Variants in Nicotine Addiction and Alcohol Metabolism Genes, Oral Cancer Risk and the Propensity to Smoke and Drink Alcohol: A Replication Study in India

Background: Genetic variants in nicotinic acetylcholine receptor and alcohol metabolism genes have been associated with propensity to smoke tobacco and drink alcohol, respectively, and also implicated in genetic susceptibility to head and neck cancer. In addition to smoking and alcohol, tobacco chewing is an important oral cancer risk factor in India. It is not known if these genetic variants influence propensity or oral cancer susceptibility in the context of this distinct etiology. Methods: We examined 639 oral and pharyngeal cancer cases and 791 controls from two case-control studies conducted in India. We investigated six variants known to influence nicotine addiction or alcohol metabolism, including rs16969968 (CHRNA5), rs578776 (CHRNA3), rs1229984 (ADH1B), rs698 (ADH1C), rs1573496 (ADH7), and rs4767364 (ALDH2). Results: The CHRN variants were associated with the number of chewing events per day, including in those who chewed tobacco but never smoked (P = 0.003, P = 0.01 for rs16969968 and rs578776 respectively). Presence of the variant allele contributed to approximately 13% difference in chewing frequency compared to non-carriers. While no association was observed between rs16969968 and oral cancer risk (OR = 1.01, 95% CI = 0.83-1.22), rs578776 was modestly associated with a 16% decreased risk of oral cancer (OR = 0.84, 95% CI = 0.72-0.98). There was little evidence for association between polymorphisms in genes encoding alcohol metabolism and oral cancer in this population. Conclusion: The association between rs16969968 and number of chewing events implies that the effect on smoking propensity conferred by this gene variant extends to the use of smokeless tobacco.