Gene-gene interactions lead to higher risk for development of type 2 diabetes in a Chinese Han population: a prospective nested case-control study.

Background: The purpose of this study was to evaluate the effect of single-nucleotide polymorphisms (SNPs) of the GCKR and G6PC2 genes on risk for type 2 diabetes and the SNP-SNP and haplotype-based interactions between these genes.

Methods: Subjects of this nested case-control study were selected from a prospective cohort residing in the rural area of Luoyang city in China. Cases (n = 538) were individually matched with controls. Six SNPs in the GCKR and G6PC2 genes were selected and genotyped using an SNPscan™ kit. Stratified Cox proportional hazards regression models were used to generate odds ratios (ORs) and 95% confidence intervals (CI) for different genotype models for the risk of T2DM. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the interactions between two genes with among six SNPs. The linkage disequilibrium (LD) analysis and the haplotype analysis were carried out by SHEsis online.

Results: We found that the C allele of rs780094 was associated with increased risk for T2DM in Han Chinese population. However, the rs492594-C allele in G6PC2 was associated with a decreased risk of T2DM. We also found a significant SNP-SNP interaction between rs2293572 and rs492594, and the CCCCGC and CGCCCA haplotypes significantly increased the risk of T2DM, however, the CCCCCA haplotype had lower susceptibility to T2DM.

Conclusion: The results suggest that the GCKR and G6PC2 genes may contribute to the risk of T2DM independently and/or in an interactive manner in the Han Chinese population.