Peripheral blood gene expression stratifies rate of progression to type 1 diabetes in autoantibody-positive children in the TEDDY study

TL;DR

Researchers found that gene expression in blood can predict how quickly children with diabetes antibodies will develop type 1 diabetes.

Contribution

A 20-gene signature was identified to stratify progression rates to type 1 diabetes in autoantibody-positive children.

Findings

Progressors showed gene expression enriched for MHC class II and immune response pathways after seroconversion.

SMARCA4 was identified as a central hub in protein–protein interaction networks linked to diabetes progression.

A 20-gene signature stratified progression rates into fast or slow categories.

Abstract

In type 1 diabetes, autoimmune destruction of pancreatic β cells results in insulin deficiency, leading to hyperglycemia. Islet autoantibodies, which precede autoimmune progression, usually develop years before diabetes onset, although some individuals develop diabetes without them. However, not all children who develop islet antibodies progress to diabetes, and they do not all progress at the same rate. Genomic markers may help identify high-risk children for early intervention.

Using gene expression profiles derived from peripheral blood mononuclear cells collected from 62 high-risk, islet autoantibody-positive children in the TEDDY cohort study, of whom 56 progressed to diabetes, we identified differentially expressed genes, pathways, and protein–protein interactions associated with progression from islet autoantibody seropositivity to the clinical onset of diabetes.

After seroconversion, progressors were distinguished by a peripheral blood gene expression profile enriched for MHC class II-related functions and immune response pathways. Within protein– protein interaction (PPI) networks, we identified SMARCA4 as the central hub and found that its expression stratified progression to type 1 diabetes after seroconversion. Differentially expressed genes in the PPI networks were also highly connected to type 1 diabetes drug–gene targets, particularly JAK2.

The enrichment of MHC class II-related functions and immune response pathways after seroconversion highlights immune activation in progressors, whose rate of progression could be stratified as fast or slow based on a 20-gene signature, which warrants confirmation in an independent cohort.

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