Abstract

Objective: Monocytes in childhood-onset type 1 diabetes show distinct gene expression. We hypothesize that monocyte activation in monozygotic (MZ) twin pairs discordant for childhood-onset type 1 diabetes could reflect distinct stages of the disease process including diabetes susceptibility (differences between twins, both diabetic and non-diabetic, and controls) and/or disease progression (differences between diabetic and non-diabetic twins).

Research Design and Methods: We studied patterns of inflammatory gene expression in peripheral blood monocytes of MZ twin pairs (n=10 pairs) discordant for childhood-onset type 1 diabetes, normal control twin pairs (n=10 pairs) and healthy control subjects (n=51) using quantitative-PCR (Q-PCR). We tested the 24 genes previously observed by whole genome analyses and verified by Q-PCR in autoimmune diabetes and performed a hierarchical cluster analysis.

Results: Of 24 genes abnormally expressed in childhood-onset type 1 diabetes, we re-validated abnormal expression in 16 of them in diabetic twins, including distinct sets of down-regulated (p<0.03) and up-regulated genes (p<0.02). Of these 16 genes: 13 were abnormally expressed in non-diabetic twins, implicating these genes in diabetes susceptibility (p<0.044 for all). Cluster analysis of monocyte gene-expression in non-diabetic twins identified two distinct, mutually exclusive clusters, while diabetic twins had a network of positively correlated genes.

Conclusions: Patients with childhood-onset type 1 diabetes show abnormal monocyte gene-expression levels with an altered gene-expression network due to gene-environment interaction. Importantly, perturbed gene-expression clusters were also detected in non-diabetic twins, implicating monocyte abnormalities in susceptibility to diabetes.