title: 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.
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
authors.forename: Vincent Kwok Lim
authors.initials: VK
authors.lastname: Lam
authors.forename: Ronald Ching Wan
authors.initials: RC
authors.lastname: Ma
authors.forename: Heung Man
authors.initials: HM
authors.lastname: Lee
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Hiroto
authors.initials: H
authors.lastname: Furuta
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Claudia Ha Ting
authors.initials: CH
authors.lastname: Tam
authors.forename: Xueling
authors.initials: X
authors.lastname: Sim
authors.forename: Daniel Peng-Keat
authors.initials: DP
authors.lastname: Ng
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Tien-Yin
authors.initials: TY
authors.lastname: Wong
authors.forename: E Shyong
authors.initials: ES
authors.lastname: Tai
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.forename: Nelson Leung Sang
authors.initials: NL
authors.lastname: Tang
authors.forename: Jean
authors.initials: J
authors.lastname: Woo
authors.forename: Ping Chung
authors.initials: PC
authors.lastname: Leung
authors.forename: Alice Pik Shan
authors.initials: AP
authors.lastname: Kong
authors.forename: Risa
authors.initials: R
authors.lastname: Ozaki
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Jia
authors.forename: Hong Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Kishio
authors.initials: K
authors.lastname: Nanjo
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Maggie Chor Yin
authors.initials: MC
authors.lastname: Ng
authors.forename: Wing-Yee
authors.initials: WY
authors.lastname: So
authors.forename: Juliana Chung Ngor
authors.initials: JC
authors.lastname: Chan
mesh_terms: D044466:Asian People; D043423:Carboxypeptidase H / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D058228:Islet Amyloid Polypeptide / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D058228:Islet Amyloid Polypeptide; D043423:Carboxypeptidase H; D007339:Insulysin