Inclusion of a gene-environment interaction between alcohol consumption and the aldehyde dehydrogenase 2 genotype in a risk prediction model for upper aerodigestive tract cancer in Japanese men.

The well-known gene-environment interaction between alcohol consumption and aldehyde dehydrogenase 2 (ALDH2) genotype in upper aerodigestive tract cancer risk may improve our ability to identify high-risk subjects. Here, we developed and validated risk prediction models for this cancer in Japanese men and evaluated whether adding the gene-environment interaction to the model improved the predictive performance. We developed two case-cohort datasets in the Japan Public Health Center-based Prospective Study: one from subjects in the baseline survey for model development (108 cases and 4049 subcohort subjects) and the second from subjects in the 5-year follow-up survey for model validation (31 cases and 1527 subcohort subjects). We developed an environmental model including age, smoking status, and alcohol consumption, and a gene-environment interaction model including age, smoking status, and the combination of alcohol consumption and the ALDH2 genotype. We found a statistically significant gene-environment interaction for alcohol consumption and the ALDH2 genotype. The c-index for the gene-environment interaction model (0.71) was slightly higher than that for the environmental model (0.67). The values of integrated discrimination improvement and net reclassification improvement for the gene-environment interaction model were also slightly higher than those for the environmental model. Goodness-of-fit tests suggested that the models were well calibrated. Results from external model validation by the 5-year follow-up survey were consistent with those from the model development by the baseline survey. The addition of a gene-environment interaction to a lifestyle-based model might improve the performance to estimate the probability of developing upper aerodigestive tract cancer for Japanese men.