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

Autor: Alice P.S. Kong, Ronald C.W. Ma, Andrew P. Morris, Hiroto Furuta, Cheng Hu, Juliana C.N. Chan, Daniel P.K. Ng, Ying Wang, Kishio Nanjo, Xueling Sim, Jean Woo, Kyong Soo Park, Nelson L.S. Tang, Weiping Jia, Tien Yin Wong, Risa Ozaki, Gang Xu, E. Shyong Tai, Vincent K. L. Lam, Ping-Chung Leung, Heung Man Lee, Maggie C.Y. Ng, Wing-Yee So, Claudia H. T. Tam, Hong Kyu Lee, Jianjun Liu
Přispěvatelé: Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM)
Rok vydání: 2012
Předmět:
Candidate gene
lcsh:Medicine
Gene Expression
Genome-wide association study
Type 2 diabetes
Insulysin
Biochemistry
HHEX
MELLITUS
0302 clinical medicine
Endocrinology
ENDOPLASMIC-RETICULUM STRESS
Insulin-degrading enzyme
TRANSCRIPTION FACTOR
lcsh:Science
METABOLIC SYNDROME
RISK
Genetics
0303 health sciences
Multidisciplinary
INSULIN
3. Good health
Islet Amyloid Polypeptide
OBESITY
Medicine
Beta cell
Research Article
medicine.medical_specialty
endocrine system
SUSCEPTIBILITY LOCI
030209 endocrinology & metabolism
Single-nucleotide polymorphism
Biology
Polymorphism
Single Nucleotide
Molecular Genetics
03 medical and health sciences
Asian People
HUMAN PANCREATIC-ISLETS
Internal medicine
medicine
Humans
Gene Regulation
Gene
Genetic Association Studies
030304 developmental biology
Diabetic Endocrinology
lcsh:R
Islet amyloid polypeptide processing
Carboxypeptidase H
Computational Biology
Human Genetics
Diabetes Mellitus Type 2
medicine.disease
Hormones
Metabolism
Diabetes Mellitus
Type 2
Genetics of Disease
Genetic Polymorphism
lcsh:Q
Population Genetics
Zdroj: PLoS ONE
ResearcherID
PLoS ONE, 8(6):e62378. PUBLIC LIBRARY SCIENCE
PLoS ONE, Vol 8, Iss 6, p e62378 (2013)
PLoS ONE 8:e62378 (2013)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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