Diversity of interacting proteins in type 2 diabetes
Genomic analysis has turned up around 100 loci that are linked to T2D. Moreover, evidence suggests that these genetic components influence transcription and not gene function. To maximise the applications in a clinical setting, the T2DCREBBP (Defining the molecular basis of type 2 diabetes predisposition through targeted sequencing of the CREBBP-interacting gene network) project has developed new analysis methods. These have identified and prioritised new T2D susceptibility loci. Project researchers applied a network analysis pipeline to evaluate the relationship between T2D association and protein-protein interaction (PPi) networks connected to the genes. The diverse sets under analysis added up to a total of more than 70 000 cases and included exome array data and exome sequencing data as well as genome association studies and custom array genotype data. Results of the analysis have shown that there are a number of protein complexes that are enriched in T2D cases. These networks feature proteins related to respiratory function and the regulation of insulin secretion. Very significant is the discovery of one protein related to insulin receptor activation in adipose tissue. This provides a link between adipose tissue and T2D, and a paper is under review at Nature on this topic. In total, the researchers have sequenced around 55 000 exomes, making this one of the biggest exome data sets available. Joint analysis will enable further testing of the overlap between the variation in coding sequence and increase in PPi and evaluation of the link between rare variant signal aggregation and pathogenesis. Increasing the potential of prediction of novel networks, the T2DCREBBP team has developed a more comprehensive PPi analysis framework. Moreover, the methodology is applicable to other complex diseases. Project work has significantly increased the knowledge base for T2D, a disease with a large social and economic burden in the EU.
Keywords
Type 2 diabetes, T2D, T2DCREBBP, protein-protein interaction, exome, insulin, complex diseases
