Identification of Novel Type 1 Diabetes Candidate Genes by Integrating Genome-Wide Association Data, Protein-Protein Interactions, and Human Pancreatic Islet Gene Expression
Open accessAbstract
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.
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Common genetic variants in PLCG2 link the enzyme to type 1 diabetes and venous thromboembolism.
“Common genetic variants in PLCG2 also link the enzyme to type 1 diabetes (119) and venous thromboembolism (120), which could have a shared autoimmune etiology.”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [119]
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- Authors
- Bergholdt, R., Brorsson, C., Palleja, A., Berchtold, L. A., Fløyel, T., Bang-Berthelsen, C. H., Frederiksen, K. S., Jensen, L. J., Størling, J., & Pociot, F.
- Affiliations
- Hagedorn Research Institute, Gentofte, Denmark
- Glostrup Hospital (DK)
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Glostrup Research Institute, Glostrup University Hospital, Glostrup, Denmark
- Novo Nordisk (Denmark) (DK)
- University of Copenhagen (DK)
- Lund University (SE)
- Corresponding author
- Pociot, Flemming
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2012-03-14
- Volume
- 61
- Issue
- 4
- Pages
- 954-962
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3314366
- OpenAlex
- W2156167884
- Cited by
- 125
- References
- 51
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 12 · 2021: 10 · 2020: 12 · 2019: 6 · 2018: 9 · 2017: 13 · 2016: 12 · 2015: 9 · 2014: 11 · 2013: 14 · 2012: 4
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Novo Nordisk Fonden
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK062418, DP3DK085678)
- National Institute of Child Health and Human Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- type 1 diabetes, candidate genes, genetic susceptibility loci, protein-protein interaction network, pancreatic islets, inflammatory cytokines, gene expression profiling, single nucleotide polymorphisms, CD83, IFNGR1, TRAF3IP2, PLCγ2, MYO1B, CXCR7
- MeSH terms
- Diabetes Mellitus, Type 1, Gene Expression Regulation, Humans, Islets of Langerhans, Genome, Human, Gene Expression Profiling, Protein Interaction Maps
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