Chronic alcohol intake is associated with type 2 diabetes mellitus (T2DM) as an independent risk factor, and it has also been considered to be related with increased adipogenesis, impaired glucose tolerance, and insulin resistance [2]. However, the underlying molecular mechanisms behind physiological and pathological entities have not been fully explored.

In our study, we conducted the approximate conditional analysis on multiple diverse effects. We confirmed that the associated signals of two variants (rs11065756 and rs2074356) in CCDC63 and C12orf51 were only slightly diminished after adjustment for alcohol consumptionin T2DM, fasting plasma glucose, and homeostatic model assessment-B traits, indicating that there was no evidence for the substantial attenuation in statistical causal inference. These results suggested that the newly identified T2DM loci were not simply secondary to the alcohol effects.

Indeed, a previous genome-wide study showed that the two loci were predominantly associated with the amount of alcohol consumed in two population-based cohorts including heavy drinkers (~40%) [3]. Several studies have reported that moderate alcohol intake is associated with decreased risk of T2DM [4,5,6]. Recent studies have demonstrated that alcohol intake is associated with widespread changes in DNA methylation as an epigenetic factor [7,8]. Given the phenotypic and genotypic heterogeneity between T2DM and alcohol intake, further integrated multianalyses will be needed to determine influence of metastable epialleles on T2DM risk [9]. Taken together, our findings suggest that the two novel variants influencing T2DM have impacts on alcohol-independent T2DM risk. The identification of these loci provides additional clues regarding the pleiotropic effects associated with variation in the 12q24 region of the human genome.