Association of TCF7L2 gene polymorphisms, methylation, and gene-environment interaction with type 2 diabetes mellitus risk: A nested case-control study in the Rural Chinese Cohort Study

Background: To assess the associations of single-nucleotide polymorphisms (SNPs) and methylation of transcription factor 7-like 2 (TCF7L2) gene with type 2 diabetes mellitus (T2DM) risk and further explore the interactions among SNPs, methylation, and environmental factors involved in T2DM risk.

Methods: We conducted a nested case-control study with 290 pairs of T2DM cases and matched controls. We genotyped 3 SNPs of TCF7L2 in all included participants and tested 14 CpG loci of TCF7L2 in 76 pairs of cases and controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for T2DM risk according to SNPs and methylation of TCF7L2. Multifactor dimensionality reduction (MDR) analysis was used to explore the potential TCF7L2 gene-environment interactions in T2DM risk.

Results: We found no statistically significant association between the TCF7L2 polymorphisms and T2DM risk. We observed significant positive associations of methylation at CpG5 and CpG7_8 with T2DM risk. For each 1% increase in DNA methylation at CpG5 and CpG7_8, T2DM risk increased 12% (OR 1.12, 95% CI 1.01-1.25) and 32% (OR 1.32, 95% CI 1.07-1.63), respectively. Additionally, MDR analyses identified significant SNP-environment interactions among rs290487, alcohol drinking, and hypertension and methylation-environment interactions among CpG5, CpG7_8 and hypertension (P <0.05).

Conclusions: TCF7L2 polymorphisms were not independently associated with T2DM risk. However, TCF7L2 methylation were positively associated with T2DM risk in rural Chinese adults. Interactions among TCF7L2 polymorphisms, TCF7L2 methylation and environmental factors also suggest a possible etiologic pattern for T2DM.