Specific gene expression signature associated with development of autoimmune type-I diabetes using whole-blood microarray analysis

Abstract

Understanding the pathogenesis of type-I diabetes (T1D) is hindered in humans by the long autoimmune process occurring before clinical onset and by the difficulty to study the pancreas directly. Alternatively, exploring body fluids and particularly peripheral blood can provide some insights. Indeed, circulating cells can function as 'sentinels', with subtle changes in gene expression occurring in association with disease. Therefore, we investigated the gene expression profiles of circulating blood cells using Affymetrix microarrays. Whole-blood samples from 20 first-degree relatives of T1D children with autoimmune diabetes-related antibodies, 19 children immediately after the onset of clinical T1D and 20 age-and sex-matched healthy controls were collected in PAXgene tubes. A global gene expression analysis with MDS approach allowed the discrimination of pre-diabetic subjects, diabetic patients and healthy controls. Univariate statistical analysis highlighted 107 distinct genes differently expressed between these three groups. Two major gene expression profiles were characterized, including type-I IFN-regulated genes and genes associated with biosynthesis and oxidative phosphorylation. Our results showed the presence of early functional modifications associated with T1D, which could help to understand the disease and suggest possible avenues for therapeutic interventions.

Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

“…In agreement with our results, Reynier et al (35) recently reported that 12 IFN response genes are upregulated in the whole blood of 30% of autoantibody-positive prediabetic children, but not in healthy control subjects or recently diagnosed patients. Our data indicate that the IFN response can be detected before the appearance of autoantibodies (Fig.…”

Global gene expression changes in type 1 diabetes: Insights into autoimmune response in the target organ and in the periphery

“…The overexpression of IL-1 regulated genes in T1D PBMCs is noteworthy, as well as chemotaxis and signalling genes, and a downregulation of transcripts corresponding to genes of apoptosis, cell cycle and proteasome [18,19]. Recently the expression profile not only for PBMCs but also for whole blood has been defined [20]. Interestingly, whole blood transcriptome from individuals at a prediabetic stage show an upregulation of IFN-responsive genes, a pathway also altered in autoimmune diseases such as systemic lupus erithematosus (SLE) [21] or Sjögren syndrome (SSj) [22].…”

Frontiers in Preclinical Safety Biomarkers

“…In particular, the proposed mRNA and miRNA markers of myocardial infarction are unlikely to compare favorably with cardiac troponins, which are sensitive and specific markers of cardiac damage (Muller et al 2011;Liangos et al 2010). The proposed whole blood signatures for autoimmune diseases, Alzheimer's disease, and sepsis are either preliminary results or did not lead to the development of accepted clinical biomarkers (Reynier et al 2010;Batliwalla et al 2005;Tan et al 2006;Grunblatt et al 2009;Booij et al 2011;Sutherland et al 2011). In our laboratory, the attempt to identify a whole blood transcriptomic signature of endothelial damage in four rat models was inconclusive because of the preponderance of mRNA shifts reflecting the shifts in the major populations of white blood cells (unpublished data).…”