Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes
Type 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes by con...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-04-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fgene.2017.00043/full |
| _version_ | 1829138186904797184 |
|---|---|
| author | Søren Brunak Søren Brunak Helle Krogh Pedersen Valborg Gudmundsdottir |
| author_facet | Søren Brunak Søren Brunak Helle Krogh Pedersen Valborg Gudmundsdottir |
| author_sort | Søren Brunak |
| collection | DOAJ |
| description | Type 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes by considering their biological context, such as tissue-specific protein interaction partners. Pancreatic islets are a key T2D tissue and many of the known genetic risk variants lead to impaired islet function, hence a better understanding of the islet-specific dysregulation in the disease-state is essential to unveil the full potential of person-specific profiles. Here we identify 3,692 overlapping pancreatic islet protein complexes (containing 10,805 genes) by integrating islet gene and protein expression data with protein interactions. We found 24 of these complexes to be significantly enriched for genes associated with diabetic phenotypes through heterogeneous evidence sources, including genetic variation, methylation, and gene expression in islets. The analysis specifically revealed ten T2D candidate genes with probable roles in islets (ANPEP, HADH, FAM105A, PDLIM4, PDLIM5, MAP2K4, PPP2R5E, SNX13, GNAS, and FRS2), of which the last six are novel in the context of T2D and the data that went into the analysis. Fifteen of the twenty-four complexes were further enriched for combined genetic associations with glycemic traits, exemplifying how perturbation of protein complexes by multiple small effects can give rise to diabetic phenotypes. The complex nature of T2D ultimately prompts an understanding of the individual patients at the network biology level. We present the foundation for such work by exposing a subset of the global interactome that is dysregulated in T2D and consequently provides a good starting point when evaluating an individual's alterations at the genome, transcriptome, or proteome level in relation to T2D in clinical settings. |
| first_indexed | 2024-12-14T19:12:16Z |
| format | Article |
| id | doaj.art-3e0026cc1d30403f8f0797a3e69cbb6b |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-14T19:12:16Z |
| publishDate | 2017-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-3e0026cc1d30403f8f0797a3e69cbb6b2022-12-21T22:50:41ZengFrontiers Media S.A.Frontiers in Genetics1664-80212017-04-01810.3389/fgene.2017.00043258394Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 DiabetesSøren Brunak0Søren Brunak1Helle Krogh Pedersen2Valborg Gudmundsdottir3Department of Bio and Health Informatics, Technical University of DenmarkKgs Lyngby, DenmarkDisease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of CopenhagenCopenhagen, DenmarkDepartment of Bio and Health Informatics, Technical University of DenmarkKgs Lyngby, DenmarkDepartment of Bio and Health Informatics, Technical University of DenmarkKgs Lyngby, DenmarkType 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes by considering their biological context, such as tissue-specific protein interaction partners. Pancreatic islets are a key T2D tissue and many of the known genetic risk variants lead to impaired islet function, hence a better understanding of the islet-specific dysregulation in the disease-state is essential to unveil the full potential of person-specific profiles. Here we identify 3,692 overlapping pancreatic islet protein complexes (containing 10,805 genes) by integrating islet gene and protein expression data with protein interactions. We found 24 of these complexes to be significantly enriched for genes associated with diabetic phenotypes through heterogeneous evidence sources, including genetic variation, methylation, and gene expression in islets. The analysis specifically revealed ten T2D candidate genes with probable roles in islets (ANPEP, HADH, FAM105A, PDLIM4, PDLIM5, MAP2K4, PPP2R5E, SNX13, GNAS, and FRS2), of which the last six are novel in the context of T2D and the data that went into the analysis. Fifteen of the twenty-four complexes were further enriched for combined genetic associations with glycemic traits, exemplifying how perturbation of protein complexes by multiple small effects can give rise to diabetic phenotypes. The complex nature of T2D ultimately prompts an understanding of the individual patients at the network biology level. We present the foundation for such work by exposing a subset of the global interactome that is dysregulated in T2D and consequently provides a good starting point when evaluating an individual's alterations at the genome, transcriptome, or proteome level in relation to T2D in clinical settings.http://journal.frontiersin.org/article/10.3389/fgene.2017.00043/fulldiabetesdata integrationprotein complexestissue specificitypancreatic isletspatient network biology |
| spellingShingle | Søren Brunak Søren Brunak Helle Krogh Pedersen Valborg Gudmundsdottir Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes Frontiers in Genetics diabetes data integration protein complexes tissue specificity pancreatic islets patient network biology |
| title | Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes |
| title_full | Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes |
| title_fullStr | Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes |
| title_full_unstemmed | Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes |
| title_short | Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes |
| title_sort | pancreatic islet protein complexes and their dysregulation in type 2 diabetes |
| topic | diabetes data integration protein complexes tissue specificity pancreatic islets patient network biology |
| url | http://journal.frontiersin.org/article/10.3389/fgene.2017.00043/full |
| work_keys_str_mv | AT sørenbrunak pancreaticisletproteincomplexesandtheirdysregulationintype2diabetes AT sørenbrunak pancreaticisletproteincomplexesandtheirdysregulationintype2diabetes AT hellekroghpedersen pancreaticisletproteincomplexesandtheirdysregulationintype2diabetes AT valborggudmundsdottir pancreaticisletproteincomplexesandtheirdysregulationintype2diabetes |