Abnormal Monocyte-Related Signatures in Type 1 Diabetes; A Study of Identical Twins
Abstract Number: 313-OR
Authors: HURIYA BEYAN, HARM J. DE WITT, HEMMO A. DREXHAGE, RICHRAD D. LESLIE, London, UK, United Kingdom, Rotterdam, The Netherlands
Institutions: London, UK, United Kingdom; Rotterdam, Netherlands
Results: Type 1 diabetes (T1DM) is probably due to an aggressive adaptive immune response but the innate immune system could be relevant since monocytes infiltrate the islets. We initially detected changes in T1DM monocytes including a cluster of altered genes expression profiles (unpublished). Our present aim was to identify monocyte-related biomarkers in identical twin pairs discordant for T1DM (only one twin with diabetes) to determine and validate monocyte gene clusters which are diabetes-associated or associated with disease-susceptibly.
We studied 14 identical twin pairs (all discordant for T1DM) 6 male; mean age of 37 years (range17-53), mean disease duration 20.5 years (7-44) and 13 normal identical twin pairs, 7 male; mean age of 37 (23-55 years). Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll. Monocytes were isolated from PBMC by MACS-CD14 separation. Real-time quantitative PCR was preformed on extracted RNA for 14 candidate genes identified using Affymetrix plus appropriate controls including Able gene (housekeeping gene).
Abnormal expression levels of 11 monocyte genes were validated, encompassing changes in monocyte pro-inflammatory signatures, MAP kinase pathway, cell adhesion/motility and immune regulation. Abnormal levels of gene expression were detected either in the diabetic twin alone (e.g. FABP5, MAPK6, CD9, CDC42, STX1A), or in both diabetic and non-diabetic twins (e.g. CCL2, CCL7, DHRS, HSP70, SDR, DHRS, PTPN7, EMP1)(all differences p<0.02); the latter having altered expression of a different gene set but gene expression levels all being strongly correlated between twins of a pair (r >0.78) and not altered in type 2 diabetes excluding a hyperglycaemic effect.
In summary, these results both identify and validate monocyte signatures of altered gene expression levels associated with T1DM which are either familial or disease specific, and in neither case associated with type 2 diabetes. Thus we identified both disease biomarkers as well as potential targets for therapeutic intervention.