RT Journal Article
SR Electronic
T1 Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity – indications of immune cell activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 167676
DO 10.1101/167676
A1 M. Laimighofer
A1 R. Lickert
A1 R. Fürst
A1 F. J. Theis
A1 C. Winkler
A1 E. Bonifacio
A1 A.-G. Ziegler
A1 J. Krumsiek
YR 2017
UL http://biorxiv.org/content/early/2017/07/24/167676.abstract
AB Background Birth by Cesarean section increases the risk of developing type 1 diabetes later in life; however, the underlying molecular mechanisms of this effect remain unclear. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system.Methods We analyzed gene expression of peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes (n = 109). We investigated effects of Cesarean section on gene expression profiles of children in the first year of life using a generalized additive mixed model to account for the longitudinal data structure. To investigate the effect of islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns of Cesarean section and islet autoimmunity at the gene expression level.Results We identified two differentially expressed pathways in children born by Cesarean section: the pentose phosphate pathway and pyrimidine metabolism, both involved in nucleotide synthesis and cell proliferation. Islet autoantibody analysis revealed multiple differentially expressed pathways generally involved in immune processes, including both of the above-mentioned nucleotide synthesis pathways. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. In addition, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes.Conclusions We identified coherent gene expression signatures for Cesarean section, an early risk factor for type 1 diabetes, and islet autoantibodies positivity, an obligatory stage of autoimmune response prior to the development of type 1 diabetes. Both transcriptional signatures were correlated with changes in gene expression during the activation of CD4+ T lymphocytes, reflecting common molecular changes in immune cell activation.PBMCperipheral blood mononuclear cellsGAMMgeneralized linear mixed model