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Complex disease interventions from a network model for type 2 diabetes
Deniz Rende1, Nihat Baysal, Betul Kirdar
1Department of Materials Science and Engineering, Rensselaer Polytechnic Institute, Troy, New York, United States of America. rended3@rpi.edu
Abstract:
There is accumulating evidence that the proteins encoded by the genes associated with a common disorder interact with each other, participate in similar pathways and share GO terms. It has been anticipated that the functional modules in a disease related functional linkage network are informative to reveal significant metabolic processes and disease's associations with other complex disorders. In the current study, Type 2 diabetes associated functional linkage network (T2DFN) containing 2770 proteins and 15041 linkages was constructed. The functional modules in this network were scored and evaluated in terms of shared pathways, co-localization, co-expression and associations with similar diseases. The assembly of top scoring overlapping members in the functional modules revealed that, along with the well known biological pathways, circadian rhythm, diverse actions of nuclear receptors in steroid and retinoic acid metabolisms have significant occurrence in the pathophysiology of the disease. The disease's association with other metabolic and neuromuscular disorders was established through shared proteins. Nuclear receptor NRIP1 has a pivotal role in lipid and carbohydrate metabolism, indicating the need to investigate subsequent effects of NRIP1 on Type 2 diabetes. Our study also revealed that CREB binding protein (CREBBP) and cardiotrophin-1 (CTF1) have suggestive roles in linking Type 2 diabetes and neuromuscular diseases.
Insights
This study constructed a Type 2 diabetes functional linkage network. Key findings highlight circadian rhythm and nuclear receptor roles in disease pathophysiology and links to other metabolic and neuromuscular disorders.
Area of Science:
- Genomics
- Systems Biology
- Metabolic Disorders
Background:
- Proteins encoded by disease-associated genes often interact and share pathways.
- Functional modules in disease networks can reveal metabolic processes and disease comorbidities.
Purpose of the Study:
- To construct and analyze a functional linkage network for Type 2 diabetes (T2DFN).
- To identify key biological pathways and protein associations involved in T2DFN pathophysiology.
- To explore T2DFN's links to other metabolic and neuromuscular disorders.
Main Methods:
- Construction of a Type 2 diabetes associated functional linkage network (T2DFN) with 2770 proteins and 15041 linkages.
- Scoring and evaluation of functional modules based on shared pathways, co-localization, co-expression, and disease associations.
- Analysis of overlapping members in top-scoring modules.
Main Results:
- Circadian rhythm and nuclear receptor actions in steroid and retinoic acid metabolism are significantly implicated in Type 2 diabetes.
- Shared proteins established associations between Type 2 diabetes and other metabolic/neuromuscular disorders.
- Nuclear receptor NRIP1 identified as crucial for lipid/carbohydrate metabolism; CREBBP and CTF1 linked T2D to neuromuscular diseases.
Conclusions:
- The T2DFN analysis provides insights into Type 2 diabetes pathophysiology, including circadian rhythm and nuclear receptor involvement.
- Protein interactions reveal connections between Type 2 diabetes and other complex diseases.
- NRIP1, CREBBP, and CTF1 are highlighted as potential key players in Type 2 diabetes and its comorbidities.
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