Identification of Novel Type 1 Diabetes Candidate Genes by Integrating Genome-Wide Association Data, Protein-Protein Interactions, and Human Pancreatic Islet Gene Expression
- Regine Bergholdt1,
- Caroline Brorsson2,
- Albert Palleja3,
- Lukas A. Berchtold1,
- Tina Fløyel2,
- Claus Heiner Bang-Berthelsen2,
- Klaus Stensgaard Frederiksen4,
- Lars Juhl Jensen3,
- Joachim Størling2 and
- Flemming Pociot2,5⇓
- 1Hagedorn Research Institute, Gentofte, Denmark
- 2Glostrup Research Institute, Glostrup University Hospital, Glostrup, Denmark
- 3Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- 4Novo Nordisk A/S, Bagsværd, Denmark
- 5Clinical Research Center/University Hospital Malmö, University of Lund, Malmö, Sweden
- Corresponding author: Flemming Pociot, .
R.B. and C.B., and L.A.B. and T.F., respectively, contributed equally to this study.
Genome-wide association studies (GWAS) have heralded a new era in susceptibility locus discovery in complex diseases. For type 1 diabetes, >40 susceptibility loci have been discovered. However, GWAS do not inevitably lead to identification of the gene or genes in a given locus associated with disease, and they do not typically inform the broader context in which the disease genes operate. Here, we integrated type 1 diabetes GWAS data with protein-protein interactions to construct biological networks of relevance for disease. A total of 17 networks were identified. To prioritize and substantiate these networks, we performed expressional profiling in human pancreatic islets exposed to proinflammatory cytokines. Three networks were significantly enriched for cytokine-regulated genes and, thus, likely to play an important role for type 1 diabetes in pancreatic islets. Eight of the regulated genes (CD83, IFNGR1, IL17RD, TRAF3IP2, IL27RA, PLCG2, MYO1B, and CXCR7) in these networks also harbored single nucleotide polymorphisms nominally associated with type 1 diabetes. Finally, the expression and cytokine regulation of these new candidate genes were confirmed in insulin-secreting INS-1 β-cells. Our results provide novel insight to the mechanisms behind type 1 diabetes pathogenesis and, thus, may provide the basis for the design of novel treatment strategies.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1263/-/DC1.
- Received September 21, 2011.
- Accepted December 27, 2011.
- © 2012 by the American Diabetes Association.
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