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To estimate the associations between single-nucleotide polymorphisms (SNPs) and methylation of KCNQ1 gene and type 2 diabetes mellitus (T2DM) risk and the interactions among SNPs, methylation, and environmental factors on T2DM risk. We genotyped five SNPs and tested methylation at 39 CpG loci of KCNQ1 in 290 T2DM cases and 290 matched controls nested in the Rural Chinese Cohort Study. Conditional logistic regression model was used to estimate the associations between SNPs and KCNQ1 methylation and T2DM risk. Multifactor dimensionality r