Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems.
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 an...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003046&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849724640787693568 |
|---|---|
| author | Josep M Mercader Montserrat Puiggros Ayellet V Segrè Evarist Planet Eleonora Sorianello David Sebastian Sergio Rodriguez-Cuenca Vicent Ribas Sílvia Bonàs-Guarch Sorin Draghici Chenjing Yang Sílvia Mora Antoni Vidal-Puig Josée Dupuis DIAGRAM Consortium Jose C Florez MITIN Consortium Antonio Zorzano David Torrents |
| author_facet | Josep M Mercader Montserrat Puiggros Ayellet V Segrè Evarist Planet Eleonora Sorianello David Sebastian Sergio Rodriguez-Cuenca Vicent Ribas Sílvia Bonàs-Guarch Sorin Draghici Chenjing Yang Sílvia Mora Antoni Vidal-Puig Josée Dupuis DIAGRAM Consortium Jose C Florez MITIN Consortium Antonio Zorzano David Torrents |
| author_sort | Josep M Mercader |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4e81f84e7ace4752a9d21bbe1e8592d7 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-4e81f84e7ace4752a9d21bbe1e8592d72025-08-20T03:10:41ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-01812e100304610.1371/journal.pgen.1003046Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems.Josep M MercaderMontserrat PuiggrosAyellet V SegrèEvarist PlanetEleonora SorianelloDavid SebastianSergio Rodriguez-CuencaVicent RibasSílvia Bonàs-GuarchSorin DraghiciChenjing YangSílvia MoraAntoni Vidal-PuigJosée DupuisDIAGRAM ConsortiumJose C FlorezMITIN ConsortiumAntonio ZorzanoDavid TorrentsType 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003046&type=printable |
| spellingShingle | Josep M Mercader Montserrat Puiggros Ayellet V Segrè Evarist Planet Eleonora Sorianello David Sebastian Sergio Rodriguez-Cuenca Vicent Ribas Sílvia Bonàs-Guarch Sorin Draghici Chenjing Yang Sílvia Mora Antoni Vidal-Puig Josée Dupuis DIAGRAM Consortium Jose C Florez MITIN Consortium Antonio Zorzano David Torrents Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. PLoS Genetics |
| title | Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. |
| title_full | Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. |
| title_fullStr | Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. |
| title_full_unstemmed | Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. |
| title_short | Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. |
| title_sort | identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003046&type=printable |
| work_keys_str_mv | AT josepmmercader identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT montserratpuiggros identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT ayelletvsegre identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT evaristplanet identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT eleonorasorianello identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT davidsebastian identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT sergiorodriguezcuenca identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT vicentribas identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT silviabonasguarch identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT sorindraghici identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT chenjingyang identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT silviamora identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT antonividalpuig identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT joseedupuis identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT diagramconsortium identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT josecflorez identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT mitinconsortium identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT antoniozorzano identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems AT davidtorrents identificationofnoveltype2diabetescandidategenesinvolvedinthecrosstalkbetweenthemitochondrialandtheinsulinsignalingsystems |