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 |
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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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