RGD Reference Report - Genetic associations of type 2 diabetes with islet amyloid polypeptide processing and degrading pathways in asian populations. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

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

Authors: 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  DIAGRAM Consortium,   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 
Citation: Lam VK, etal., PLoS One. 2013 Jun 11;8(6):e62378. doi: 10.1371/journal.pone.0062378. Print 2013.
RGD ID: 405650683
Pubmed: PMID:23776430   (View Abstract at PubMed)
PMCID: PMC3679113   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0062378   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CPEHumantype 2 diabetes mellitus  IAGP DNA:SNP:cds (rs1583645) (human)RGD 
CpeRattype 2 diabetes mellitus  ISOCPE (Homo sapiens)DNA:SNP:cds (rs1583645) (human)RGD 
CpeMousetype 2 diabetes mellitus  ISOCPE (Homo sapiens)DNA:SNP:cds (rs1583645) (human)RGD 
IDEHumantype 2 diabetes mellitus  IAGP DNA:SNP:cds (rs6583813) (human)RGD 
IdeRattype 2 diabetes mellitus  ISOIDE (Homo sapiens)DNA:SNP:cds (rs6583813) (human)RGD 
IdeMousetype 2 diabetes mellitus  ISOIDE (Homo sapiens)DNA:SNP:cds (rs6583813) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CPEHumanBeta-cell dysfunction  IAGP DNA:SNP:cds (rs1583645) (human)RGD 
IDEHumanBeta-cell dysfunction  IAGP DNA:SNP:cds (rs6583813) (human)RGD 
CPEHumanType II diabetes mellitus  IAGP DNA:SNP:cds (rs1583645) (human)RGD 
IDEHumanType II diabetes mellitus  IAGP DNA:SNP:cds (rs6583813) (human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cpe  (carboxypeptidase E)
Ide  (insulin degrading enzyme)

Genes (Mus musculus)
Cpe  (carboxypeptidase E)
Ide  (insulin degrading enzyme)

Genes (Homo sapiens)
CPE  (carboxypeptidase E)
IDE  (insulin degrading enzyme)


Additional Information