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.
Highlights
Type 2 diabetes (T2D) is characterized by abnormal beta cell biology
We examined the risk association of T2D in a family-based cohort of Hong Kong Chinese consisting of 285 subjects with diabetes and 187 without diabetes
In a subset of 85 control subjects in whom Islet amyloid polypeptide (IAPP) and insulin were measured, we examined the risk association of significant single nucleotide polymorphisms (SNPs) with beta cell function
Summary
Type 2 diabetes (T2D) is characterized by abnormal beta cell biology. Large scale genome-wide association studies (GWAS) have discovered multiple loci associated with T2D in both European [1] and Asian populations [2]. IAPP is synthesized as a prohormone (pro-IAPP) which is processed to mature IAPP in endoplasmic reticulum (ER) by several enzymes and proteins, including prohormone convertases (PCSK1, PCSK2), carboxypeptidase E (CPE) and serum amyloid P component (APCS) before cleared by the insulin-degrading enzyme (IDE). Dysregulation of these processing enzymes, increased stabilization of IAPP by APCS and reduced clearance of IAPP by IDE [6,7,8] can lead to accumulation of pro-IAPP or excessive oligomerization of IAPP [9] which can cause mitochondrial dysfunction [10] and ER stress [11]. Excessive pro-IAPP and IAPP production can lead to formation of amyloid beta sheet resulting in loss of islet structure and beta cell function [9] (Figure S1)
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