Monocyte gene-expression profiles associated with childhood-onset type 1 diabetes and disease risk: A study of identical twins
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 nondiabetic, and control subjects) and/or disease progression (differences between diabetic and nondiabetic 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 childhoodonset type 1 diabetes, we revalidated abnormal expression in 16 of them in diabetic twins including distinct sets of downregulated (P < 0.03) and upregulated (P < 0.02) genes. Of these 16 genes, 13 were abnormally expressed in nondiabetic twins, implicating these genes in diabetes susceptibility (P < 0.044 for all). Cluster analysis of monocyte gene-expression in nondiabetic 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 nondiabetic twins, implicating monocyte abnormalities in susceptibility to diabetes.
|Persistent URL||dx.doi.org/10.2337/db09-1433, hdl.handle.net/1765/27658|
Beyan, H., Drexhage, R.C., Nieuwenhuijsen, L.V.D.H., de Wit, H.J., Padmos, R.C., Schloot, N.C., & Leslie, R.D.. (2010). Monocyte gene-expression profiles associated with childhood-onset type 1 diabetes and disease risk: A study of identical twins. Diabetes, 59(7), 1751–1755. doi:10.2337/db09-1433