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Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

ABSTRACT: Islet amyloid polypeptide (IAPP) gene variation has recently been implicated in type 2 diabetes mellitus (T2D). However, to date, no prospective epidemiological data are available.The association between 10 IAPP tag-single nucleotide polymorphisms (tSNPs) and incident T2D was investigated in 22,715 Caucasian participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer, and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk. Haplotype-based analysis was also performed.No evidence for an association of any of the tSNPs tested or haplotypes thereof with T2D risk.If corroborated in other large, prospective studies, the present findings further suggest that the IAPP gene locus may not be useful predictor for T2D risk assessment.

SUBMITTER: Zee RY

PROVIDER: S-EPMC3055174 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

Zee Robert Y L RY Pulido-Perez Patricia P Perez-Fuentes Ricardo R Ridker Paul M PM Chasman Daniel I DI Romero Jose R JR Romero Jose R JR

Clinica chimica acta; international journal of clinical chemistry 20110108 9-10

<h4>Background</h4>Islet amyloid polypeptide (IAPP) gene variation has recently been implicated in type 2 diabetes mellitus (T2D). However, to date, no prospective epidemiological data are available.<h4>Methods</h4>The association between 10 IAPP tag-single nucleotide polymorphisms (tSNPs) and incident T2D was investigated in 22,715 Caucasian participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer, and diabetes at baseline. During a 13-y ...[more]

PMID: 21219896

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Project description:A leading hypothesis for the decimation of insulin-producing ?-cells in type 2 diabetes attributes the cause to islet amyloid polypeptide (IAPP) for its deleterious effects on the cell membranes. This idea has produced extensive investigations on human IAPP (hIAPP) and its interactions with lipid bilayers. However, it is still difficult to correlate the peptide-lipid interactions with its effects on islet cells in culture. The hIAPP fibrils have been shown to interact with lipids and damage lipid bilayers, but appear to have no effect on islet cells in culture. Thus, a modified amyloid hypothesis assumes that the toxicity is caused by hIAPP oligomers, which are not preamyloid fibrils or protofibrils. However, so far such oligomers have not been isolated or identified. The hIAPP monomers also bind to lipid bilayers, but the mode of interaction is not clear. Here, we performed two types of experiments that, to our knowledge, have not been done before. We used x-ray diffraction, in conjunction with circular dichroism measurement, to reveal the location of the peptide bound to a lipid bilayer. We also investigated the effects of hIAPP on giant unilamellar vesicles at various peptide concentrations. We obtained the following qualitative results. Monomeric hIAPP binds within the headgroup region and expands the membrane area of a lipid bilayer. At low concentrations, such binding causes no leakage or damage to the lipid bilayer. At high concentrations, the bound peptides transform to ?-aggregates. The aggregates exit the headgroup region and bind to the surface of lipid bilayers. The damage by the surface bound ?-aggregates depends on the aggregation size. The initial aggregation extracts lipid molecules, which probably causes ion permeation, but no molecular leakage. However, the initial ?-aggregates serve as the seed for larger fibrils, in the manner of the Jarrett-Lansbury seeded-polymerization model, that eventually disintegrate lipid bilayers by electrostatic and hydrophobic interactions.

Project description: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.

Project description:Aims/hypothesisType 2 diabetes is characterised by islet amyloid and toxic oligomers of islet amyloid polypeptide (IAPP). We posed the questions, (1) does IAPP toxicity induce an islet response comparable to that in humans with type 2 diabetes, and if so, (2) what are the key transcriptional drivers of this response?MethodsThe islet transcriptome was evaluated in five groups of mice: beta cell specific transgenic for (1) human IAPP, (2) rodent IAPP, (3) human calpastatin, (4) human calpastatin and human IAPP, and (5) wild-type mice. RNA sequencing data was analysed by differential expression analysis and gene co-expression network analysis to establish the islet response to adaptation to an increased beta cell workload of soluble rodent IAPP, the islet response to increased expression of oligomeric human IAPP, and the extent to which the latter was rescued by suppression of calpain hyperactivation by calpastatin. Rank-rank hypergeometric overlap analysis was used to compare the transcriptome of islets from human or rodent IAPP transgenic mice vs humans with prediabetes or type 2 diabetes.ResultsThe islet transcriptomes in humans with prediabetes and type 2 diabetes are remarkably similar. Beta cell overexpression of soluble rodent or oligomer-prone human IAPP induced changes in islet transcriptome present in prediabetes and type 2 diabetes, including decreased expression of genes that confer beta cell identity. Increased expression of human IAPP, but not rodent IAPP, induced islet inflammation present in prediabetes and type 2 diabetes in humans. Key mediators of the injury responses in islets transgenic for human IAPP or those from individuals with type 2 diabetes include STAT3, NF-κB, ESR1 and CTNNB1 by transcription factor analysis and COL3A1, NID1 and ZNF800 by gene regulatory network analysis.Conclusions/interpretationBeta cell injury mediated by IAPP is a plausible mechanism to contribute to islet inflammation and dedifferentiation in type 2 diabetes. Inhibition of IAPP toxicity is a potential therapeutic target in type 2 diabetes.

Dataset Information

Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

Publications

Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

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