Abstract
We aimed to investigate the associations of polymorphisms in Canonical Wnt/β-catenin pathway (WNT) signaling genes (including low-density lipoprotein-related protein 5 [LRP5] and transcription factor 7-like 2 [TCF7L2] gene) and the downstream gene glucagon (GCG) and risk of type 2 diabetes mellitus (T2DM) in a Han Chinese population. We genotyped the single nucleotide polymorphisms (SNPs) for LRP5, TCF7L2 and GCG gene were genotyped in 1842 patients with T2DM and 7777 normal glucose-tolerant healthy subjects. We used multifactor dimensionality reduction (MDR) and multiplicative logistic regression adjusting for sex, age, anthropometric measurements and lipid levels to investigate the gene-gene interactions for the risk of T2DM. Among the five SNPs in LRP5, the recessive model of rs7102273 and the haplotype GCTCC were associated with T2DM risk; the haplotype GCTTC was associated with decreased risk. For TCF7L2, the rs11196218 genotype GA and the haplotype CCG, TTG, TTA were associated with T2DM risk; whereas, the haplotype CTG and TCG were associated with decreased risk. Both MDR and multiplicative logistic regression revealed potential gene–gene interactions among LRP5, TCF7L2, and GCG associated with T2DM. The WNT signaling pathway may play a significant role in risk of T2DM in Han Chinese people.
Highlights
Type 2 diabetes mellitus (T2DM) is a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbed carbohydrate, fat and protein metabolism
Hap-analysis revealed the haplotypes CCG, TTA, and TTG were associated with increased T2DM risk (OR = 1.130, 95% confidence intervals (95% CIs) = 1.040–1.228, p = 0.004; Odds ratios (ORs) = 1.392, 95% CI = 1.156–1.676, p = 0.001; OR = 1.442, 95% CI = 1.029–2.020, p = 0.002, respectively) and CTG and TCG associated with decreased disease risk
Wnt/β-catenin pathway (WNT) signals are transmitted to the WNT receptors to prevent the phosphorylation-dependent degradation of β-catenin, and it enters the nucleus with TCF to form aβ-catenin-TCF complex to regulate downstream target genes such as GCG [14]
Summary
Type 2 diabetes mellitus (T2DM) is a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbed carbohydrate, fat and protein metabolism. The WNT signaling pathway is composed of Wnts, secreted antagonists, seven transmembrane cell surface receptors (Frizzled) and co-receptors (e.g., LRP5), and beta-catenin. Ligand binding to both the Frizzled and LRP coreceptor can activate GSK-3, and lead to beta-catenin coactivating transcription factors (e.g., T-Cell Factor, TCF) to regulate the downstream proglucagon gene (e.g., GCG) resulting to GLP-1 expression [8]. GCG expressed in intestinal epithelial endocrine L-cells located on chromosome 2q24.2, encoded several proteins crucial for regulation of proglucagon and glucagon-like peptide (GLP)-1 and -2. From the functions of these three genes in regulating glucagon secretion, we hypothesized that the WNT signal pathway genes are associated with T2DM. For TCF7L2, we selected the SNP confirmed in previous studies
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