PLoS ONE (Jan 2013)

Genetic associations of type 2 diabetes with islet amyloid polypeptide processing and degrading pathways in asian populations.

  • Vincent Kwok Lim Lam,
  • Ronald Ching Wan Ma,
  • Heung Man Lee,
  • Cheng Hu,
  • Kyong Soo Park,
  • Hiroto Furuta,
  • Ying Wang,
  • Claudia Ha Ting Tam,
  • Xueling Sim,
  • Daniel Peng-Keat Ng,
  • Jianjun Liu,
  • Tien-Yin Wong,
  • E Shyong Tai,
  • Andrew P Morris,
  • DIAGRAM Consortium,
  • Nelson Leung Sang Tang,
  • Jean Woo,
  • Ping Chung Leung,
  • Alice Pik Shan Kong,
  • Risa Ozaki,
  • Wei Ping Jia,
  • Hong Kyu Lee,
  • Kishio Nanjo,
  • Gang Xu,
  • Maggie Chor Yin Ng,
  • Wing-Yee So,
  • Juliana Chung Ngor Chan

DOI
https://doi.org/10.1371/journal.pone.0062378
Journal volume & issue
Vol. 8, no. 6
p. e62378

Abstract

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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.