TY - JOUR
T1 - Genetic Associations of Type 2 Diabetes with Islet Amyloid Polypeptide Processing and Degrading Pathways in Asian Populations
AU - Lam, Vincent Kwok Lim
AU - Ma, Ronald Ching Wan
AU - Lee, Heung Man
AU - Hu, Cheng
AU - Park, Kyong Soo
AU - Furuta, Hiroto
AU - Wang, Ying
AU - Tam, Claudia Ha Ting
AU - Sim, Xueling
AU - Ng, Daniel Peng Keat
AU - Liu, Jianjun
AU - Wong, Tien Yin
AU - Tai, E. Shyong
AU - Morris, Andrew P.
AU - Tang, Nelson Leung Sang
AU - Woo, Jean
AU - Leung, Ping Chung
AU - Kong, Alice Pik Shan
AU - Ozaki, Risa
AU - Jia, Wei Ping
AU - Lee, Hong Kyu
AU - Nanjo, Kishio
AU - XU, Gang
AU - Ng, Maggie Chor Yin
AU - So, Wing Yee
AU - Chan, Juliana Chung Ngor
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/6/11
Y1 - 2013/6/11
N2 - 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 (PMeta = 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.
AB - 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 (PMeta = 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.
UR - http://www.scopus.com/inward/record.url?scp=84878907721&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0062378
DO - 10.1371/journal.pone.0062378
M3 - Journal article
C2 - 23776430
AN - SCOPUS:84878907721
SN - 1932-6203
VL - 8
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e62378
ER -
