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

Wen Zhou,Dongdong Zhang,Chongjian Wang,Lulu Zhang,Yuqian Li,Xuejiao Liu,Linlin Li,Yuanyuan Shi,Zhenxing Mao

doi:10.1186/s12944-018-0813-6

Abstract

BackgroundThe 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.MethodsSubjects 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.ResultsWe 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.ConclusionThe 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.

Highlights

The purpose of this study was to evaluate the effect of single-nucleotide polymorphisms (SNPs) of the Glucokinase regulatory protein (GCKR) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) genes on risk for type 2 diabetes and the SNP-SNP and haplotype-based interactions between these genes
Studies show that single-nucleotide polymorphisms (SNPs) of the GCKR and G6PC2 genes are associated with fasting plasma glucose (FPG) and Type 2 diabetes mellitus (T2DM) incidence, the conclusions are inconsistent in different regions. [6,7,8,9] the SNPs associated with T2DM explain only a part of the heritability
Compared with controls, the values of body mass index (BMI), waist-height ratio, FPG, family history of diabetes and the level of total cholesterol (TC), TG, were significant higher and the level of HDL-c were lower among cases at the beginning of the study

Summary

Introduction

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. With the rapidly rising prevalence of T2DM, a more systematic understanding of the natural history of the disease and its potential risk factors is urgently needed. Both genetic and environmental factors contribute to the occurrence and pathophysiology of T2DM. Studies show that single-nucleotide polymorphisms (SNPs) of the GCKR and G6PC2 genes are associated with FPG and T2DM incidence, the conclusions are inconsistent in different regions. There have been reports of the relationship between the GCKR and G6PC2 genes and FPG and T2DM, but the association between the interaction of these two genes and T2DM risk has not been reported

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