Finally, we observed a significant interactive effect of ESRα promoter methylation and HDL-C on the risk of T2DM, indicating that the level of ESRα methylation may modify the association between HDL-C and the risk of T2DM, and the risk of T2DM in participants with lower ESRα methylation is more susceptible to the alteration of HDL-C. Here, ESR1 is linked to type 2 diabetes mellitus.