TXNIP hypomethylation and its interaction with obesity and hypertriglyceridemia increase type 2 diabetes mellitus risk: a nested case‐control study

BACKGROUND: This study aims to estimate type 2 diabetes mellitus (T2DM) incidence with DNA methylation of the thioredoxin-interacting protein (TXNIP) gene and its interaction with environmental factors. MATERIALS AND METHODS: This case-control study included 286 incident T2DM cases and 286 non-T2DM controls matched by sex, age, marital status, race, and residence village nested in the Rural Chinese Cohort Study. A conditional logistic regression model was used to estimate the association of DNA methylation at TXNIP gene with T2DM risk. Also, multifactor dimensionality reduction (MDR) and classification and regression tree (CART) analyses were used to investigate the interaction between TXNIP methylation and environmental risk factors. RESULTS: Methylation levels of all five CpG loci at TXNIP gene were significantly lower in T2DM than in controls (all P /=72%, nonobesity, normal triglyceride (TG) level, and CpG4 methylation >/=83%) vs terminal node 1 (CpG3 methylation <72%) (odds ratio 95% CI 0.20, 0.10-0.40). CONCLUSIONS: TXNIP methylation is associated with T2DM incidence in a Chinese population. Interaction between TXNIP methylation and environmental factors may influence T2DM risk and needs more investigation. HIGHLIGHTS: This is the first prospective nested case-control study in rural Chinese people to estimate the association of the methylation level of the thioredoxin-interacting protein (TXNIP) gene and its interaction with type 2 diabetes mellitus (T2DM) risk. We found a significant negative association between the methylation level of TXNIP gene and T2DM incidence. Interaction among TXNIP gene hypomethylation, obesity, and hypertriglyceridemia increased the risk of T2DM.