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01.05.2011 | Article

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

verfasst von: J. M. Forbes, J. Söderlund, F. Y. T. Yap, M. Knip, S. Andrikopoulos, J. Ilonen, O. Simell, R. Veijola, K. C. Sourris, M. T. Coughlan, C. Forsblom, R. Slattery, S. T. Grey, M. Wessman, H. Yamamoto, A. Bierhaus, M. E. Cooper, P.-H. Groop

Erschienen in: Diabetologia | Ausgabe 5/2011

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Abstract

Aims/hypothesis

This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment.

Methods

We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice.

Results

The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels.

Conclusions/interpretation

These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

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Titel: Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes
verfasst von: J. M. Forbes
J. Söderlund
F. Y. T. Yap
M. Knip
S. Andrikopoulos
J. Ilonen
O. Simell
R. Veijola
K. C. Sourris
M. T. Coughlan
C. Forsblom
R. Slattery
S. T. Grey
M. Wessman
H. Yamamoto
A. Bierhaus
M. E. Cooper
P.-H. Groop
Publikationsdatum: 01.05.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 5/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2058-z

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Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

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