Systems Biology Approach Reveals Genome to Phenome Correlation in Type 2 Diabetes

Abstract

Genome-wide association studies (GWASs) have discovered association of several loci with Type 2 diabetes (T2D), a common complex disease characterized by impaired insulin secretion by pancreatic β cells and insulin signaling in target tissues. However, effect of genetic risk variants on continuous glycemic measures in nondiabetic subjects mainly elucidates perturbation of insulin secretion. Also, the disease associated genes do not clearly converge on functional categories consistent with the known aspects of T2D pathophysiology. We used a systems biology approach to unravel genome to phenome correlation in T2D. We first examined enrichment of pathways in genes identified in T2D GWASs at genome-wide or lower levels of significance. Genes at lower significance threshold showed enrichment of insulin secretion related pathway. Notably, physical and genetic interaction network of these genes showed robust enrichment of insulin signaling and other T2D pathophysiology related pathways including insulin secretion. The network also overrepresented genes reported to interact with insulin secretion and insulin action targeting antidiabetic drugs. The drug interacting genes themselves showed overrepresentation of insulin signaling and other T2D relevant pathways. Next, we generated genome-wide expression profiles of multiple insulin responsive tissues from nondiabetic and diabetic patients. Remarkably, the differentially expressed genes showed significant overlap with the network genes, with the intersection showing enrichment of insulin signaling and other pathways consistent with T2D pathophysiology. Literature search led our genomic, interactomic, transcriptomic and toxicogenomic evidence to converge on TGF-beta signaling, a pathway known to play a crucial role in pancreatic islets development and function, and insulin signaling. Cumulatively, we find that GWAS genes relate directly to insulin secretion and indirectly, through collaborating with other genes, to insulin resistance. This seems to support the epidemiological evidence that environmentally triggered insulin resistance interacts with genetically programmed β cell dysfunction to precipitate diabetes.

Bioenergetic Analysis of Single Pancreatic β-Cells Indicates an Impaired Metabolic Signature in Type 2 Diabetic Subjects

“…T2D patients and isolated diabetic islets increase insulin secretion close to normally (8) or normally (3) in response to sulfonylureas and to plasma membrane potential (⌬P) depolarization (9). This indicates an intact ATP-sensitive K ϩ -channel (K ATP ) operation and downstream insulin exocytosis, although the diverse pathways which genetic variants of susceptibility to T2D are associated with include insulin processing and secretion, but also energy metabolism or related signaling (9,10). Decreased expression levels and enzymatic activities of select glycolytic, tricarboxylic acid (TCA) cycle and oxidative phosphorylation components have been reported in T2D human islets (8,11,12), but not in all cases (13), and maximal capacity of respiration was not decreased (14).…”

Genetics, genomics and personalized medicine in Type 2 diabetes: a perspective on the Arab region

“…These networks assess both functional interactions and mathematical correlations between given data in a biological setting and provide a broader picture. Jain et al [75] have demonstrated the use of a systems biology approach for uncovering genome to phenome correlations in T2D by identifying pathways known to be associated with disease pathology. Although the field of systems biology holds promise, it is still in its nascent stage and requires extensive work to be able to map diseases in complex tissues and organ systems.…”

The pancreatic β-cell transcriptome and integrated-omics

“…GWAS studies examining single nucleotide polymorphisms have identified over 70 candidate genes potentially linked to T1D or to T2D (31-33). RNASeq has permitted tissue specific, high throughput detection of mRNA from those genetic loci.…”