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Title: Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems
Author: Mercader, Josep M.
Puiggròs, Montserrat
Segrè, Ayellet V.
Planet, Evarist
Sorianello, Eleonora
Sebastian, David
Rodriguez Cuenca, Sergio
Ribas, Vicent
Bonàs Guarch, Sílvia
Draghici, Sorin
Yang, Chenjing
Mora Fayos, Sílvia
Vidal-Puig, Antonio
Dupuis, Josée
Florez, Jose C.
Zorzano Olarte, Antonio
Torrents Arenales, David
DIAGRAM Consortium
MITIN Consortium
Keywords: Diabetis
Malalties cardiovasculars
Cardiovascular diseases
Issue Date: 6-Dec-2012
Publisher: Public Library of Science (PLoS)
Abstract: Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.
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It is part of: PLoS Genetics, 2012, vol. 8, num. 12, p. e1003046
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ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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