A Ragvin

AE Kel

Alice Pik Shan Kong

Andrew P. Morris

AV Matveyenko

BF Voight

C Lange

Cheng Hu

CJ Groves

CJ Huang

Claudia Ha Ting Tam

D Qi

Daniel Peng-Keat Ng

DF Steiner

E Zeggini

E. Shyong Tai

ET Jaikaran

Gang Xu

H Chen

H Zhao

Heung Man Lee

Hiroto Furuta

HL Zhao

Hong Kyu Lee

I Prokopenko

J Paulsson

JC Barrett

JC Chan

Jean Woo

Jianjun Liu

JK Li

JK Wolford

JP Noonan

Juliana Chung Ngor Chan

JZ Bai

K Piwernetz

KD Jeffrey

KH Liu

Kishio Nanjo

KJ Gaulton

Kyong Soo Park

LJ Martin

M He

M Stumvoll

Maggie Chor Yin Ng

MB Pepys

MC Ng

MI McCarthy

MK Kim

ML Stitzel

MS German

N Rudovich

N Utsunomiya

Nelson Leung Sang Tang

P Westermark

Ping Chung Leung

Q Yang

R Bhandare

R DerSimonian

RG Bennett

Risa Ozaki

Ronald Ching Wan Ma

S Nordman

SB Harrap

SH Kwak

Shiro Maeda

Tien-Yin Wong

TS Leak

V Steinthorsdottir

Vincent Kwok Lim Lam

Wei Ping Jia

Wing-Yee So

WP Jia

X Sim

XL Li

Xueling Sim

Y Cai

Y Furukawa

Y Wang

Ying Wang

YS Cho

PLoS ONE

PubMed

Lam, Vincent Kwok Lim

Ma, Ronald Ching Wan

Lee, Heung Man

Hu, Cheng

Park, Kyong Soo

Furuta, Hiroto

Wang, Ying

Tam, Claudia Ha Ting

Sim, Xueling

Ng, Daniel Peng-Keat

Liu, Jianjun

Wong, Tien-Yin

Tai, E. Shyong

Morris, Andrew P.

Tang, Nelson Leung Sang

Woo, Jean

Leung, Ping Chung

Kong, Alice Pik Shan

Ozaki, Risa

Jia, Wei Ping

Lee, Hong Kyu

Nanjo, Kishio

Xu, Gang

Ng, Maggie Chor Yin

So, Wing-Yee

Chan, Juliana Chung Ngor

Ostaptchouk, Jana

Wijmenga, Cisca

University of Groningen Research Database

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

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

Lam, VK

Ma, RC

Lee, HM

Hu, C

Park, KS

Furuta, H

Wang, Y

Tam, CH

Sim, X

Ng, DP

Liu, J

Wong, TY

Tai, ES

Morris, Andrew

Tang, NL

Woo, J

Leung, PC

Kong, AP

Ozaki, R

Jia, WP

Lee, HK

Nanjo, K

Xu, G

Ng, MC

So, WY

Chan, JC

Oxford University Research Archive

English

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

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 = 9.4x10(-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

NARCIS 

Morris, AP

Oxford University Research Archive (ORA)

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 = 9.4x10(-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 &gt;= 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.</p

University of Groningen

Lam Vincent Kwok Lim

Ma Ronald Ching Wan

Lee Heung Man

Hu Cheng

Park Kyong Soo

Furuta Hiroto

Wang Ying

Tam Claudia Ha Ting

Sim Xueling

Ng Daniel Peng-Keat

Liu Jianjun

Wong Tien-Yin

Tai E. Shyong

Morris Andrew P.

Tang Nelson Leung Sang

Woo Jean

Leung Ping Chung

Kong Alice Pik Shan

Ozaki Risa

Jia Wei Ping

Lee Hong Kyu

Nanjo Kishio

Xu Gang

Ng Maggie Chor Yin

So Wing-Yee

Chan Juliana Chung Ngor

Public Library of Science (PLOS)

<div>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.</div

Vincent Kwok Lim Lam (246186)

Ronald Ching Wan Ma (246193)

Heung Man Lee (246184)

Cheng Hu (44938)

Kyong Soo Park (172819)

Hiroto Furuta (420414)

Ying Wang (11406)

Claudia Ha Ting Tam (246178)

Xueling Sim (103662)

Daniel Peng-Keat Ng (225337)

Jianjun Liu (28194)

Tien-Yin Wong (159436)

E. Shyong Tai (103763)

Andrew P. Morris (145709)

Nelson Leung Sang Tang (364293)

Jean Woo (240342)

Ping Chung Leung (420415)

Alice Pik Shan Kong (420416)

Risa Ozaki (420417)

Wei Ping Jia (420418)

Hong Kyu Lee (179212)

Kishio Nanjo (420419)

Gang Xu (219455)

Maggie Chor Yin Ng (246198)

file:///data/remote/core/dit/data/public_library_of_science/pdf/7e5/ZnRwOi8vZnRwLm5jYmkubmxtLm5paC5nb3YvcHViL3BtYy9vYV9wYWNrYWdlLzhkLzc3L1BNQzM2NzkxMTMudGFyLmd6.pdf

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

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