MONOCYTE GENE-EXPRESSION PROFILES ASSOCIATED WITH CHILDHOOD-ONSET TYPE 1 DIABETES AND DISEASE RISK: A STUDY OF IDENTICAL TWINS.

  1. Richard David Leslie (r.d.g.leslie{at}qmul.ac.uk)1
  1. Blizard Institute of Cell and Molecular Science, Queen Mary, University of London, UK1
  2. Department of Immunology, Erasmus MC, Rotterdam, the Netherlands2
  3. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf and Department of Medicine/Metabolic Diseases, University Hospital, Düsseldorf Germany3

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.

Footnotes

    • Received September 28, 2009.
    • Accepted March 26, 2010.

This Article

  1. Diabetes
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db09-1433v1
    2. 59/7/1751 most recent