Genetic Associations of Type 2 Diabetes with Islet Amyloid Polypeptide Processing and Degrading Pathways in Asian Populations

Abstract

Type 2 diabetes (T2D) is a complex disease characterized by beta cell dysfunctions. Islet amyloid polypeptide (IAPP) is highly conserved and co-secreted with insulin with over 40% of autopsy cases of T2D showing islet amyloid formation due to IAPP aggregation. Dysregulation in IAPP processing, stabilization and degradation can cause excessive oligomerization with beta cell toxicity. Previous studies examining genetic associations of pathways implicated in IAPP metabolism have yielded conflicting results due to small sample size, insufficient interrogation of gene structure and gene-gene interactions. In this multi-staged study, we screened 89 tag single nucleotide polymorphisms (SNPs) in 6 candidate genes implicated in IAPP metabolism and tested for independent and joint associations with T2D and beta cell dysfunctions. Positive signals in the stage-1 were confirmed by de novo and in silico analysis in a multi-centre unrelated case-control cohort. We examined the association of significant SNPs with quantitative traits in a subset of controls and performed bioinformatics and relevant functional analyses. Amongst the tag SNPs, rs1583645 in carboxypeptidase E (CPE) and rs6583813 in insulin degrading enzyme (IDE) were associated with 1.09 to 1.28 fold increased risk of T2D (P Meta = 9.4×10−3 and 0.02 respectively) in a meta-analysis of East Asians. Using genetic risk scores (GRS) with each risk variant scoring 1, subjects with GRS≥3 (8.2% of the cohort) had 56% higher risk of T2D than those with GRS = 0 (P = 0.01). In a subcohort of control subjects, plasma IAPP increased and beta cell function index declined with GRS (P = 0.008 and 0.03 respectively). Bioinformatics and functional analyses of CPE rs1583645 predicted regulatory elements for chromatin modification and transcription factors, suggesting differential DNA-protein interactions and gene expression. Taken together, these results support the importance of dysregulation of IAPP metabolism in T2D in East Asians.

High risk of conversion to diabetes in first-degree relatives of individuals with young-onset type 2 diabetes: a 12-year follow-up analysis

“…The link between a family history of diabetes and elevated risk of Type 2 diabetes involves complex interactions of genes, common behaviours, shared environment and epigenetic modification [16]. In keeping with this, using probands with familial young-onset diabetes in our Chinese cohort, our group had identified novel risk loci associated with Type 2 diabetes [20][21][22][23][24]. In this connection, previous studies have demonstrated the influence of family history on the age of diagnosis [17].…”

“…People with young-onset diabetes are more likely to carry susceptibility genes that put them at higher risk of developing diabetes at an earlier age compared with their older counterparts [17,19]. In keeping with this, using probands with familial young-onset diabetes in our Chinese cohort, our group had identified novel risk loci associated with Type 2 diabetes [20][21][22][23][24]. Most of these variants had been replicated in other Asian populations although the effect size was reduced in more heterogeneous populations.…”

Identification of Electrostatic Hotspots at the Binding Interface of Amylin and InsulinDegrading Enzyme: A Structural and Biophysical Investigation

“…• This finding also contributes to the growing body of knowledge aimed at unraveling the intricacies of protein-protein interactions and provides a foundation for future research endeavors in the development of targeted therapeutics for metabolic disorders, particularly diabetes (T2DM) and obesity [57,58].…”

Identification of Electrostatic Hotspots at the Binding Interface of Amylin and Insulin-Degrading Enzyme: A Structural and Biophysical Investigation

“…2. This finding also contributes to the growing body of knowledge aimed at unraveling the intricacies of protein-protein interactions and provides a foundation for future research endeavors in the development of targeted therapeutics for metabolic disorders, particularly diabetes (T2DM) and obesity [57,58]. 3.…”