Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients

Saito, T.; Toda, H.; Duncan, G. N.; Jellison, S. S.; Yu, T.; Klisares, M. J.; Daniel, S.; Andreasen, A.; Leyden, L.; Hellman, M.; Shinozaki, E.; Lee, S.; Yoshino, A.; Cho, H. R.; Shinozaki, G.

doi:10.1101/729335

bioRxiv · 10.1101/729335

Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients

Saito, T.·Toda, H.·Duncan, G. N.·Jellison, S. S.·Yu, T.·Klisares, M. J.·Daniel, S.·Andreasen, A.·Leyden, L.·Hellman, M.·Shinozaki, E.·Lee, S.·Yoshino, A.·Cho, H. R.·Shinozaki, G.

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Abstract

BackgroundThe authors previously hypothesized the role of epigenetics in pathophysiology of delirium, and tested DNA methylation (DNAm) change among pro-inflammatory cytokines along with aging in blood, glia and neuron. The authors reported that DNAm level of the TNF-alpha decreases along with aging in blood and glia, but not in neuron; however, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, in the present study, DNAm differences in blood between delirium patients and controls without delirium were examined.\n\nMethodsA case-control study with 92 subjects was conducted. Whole blood samples were collected and genome-wide DNAm was measured by the Infinium HumanMethylationEPIC BeadChip arrays. The correlation between DNAm levels in the TNF-alpha and age, network analysis, and the correlation between age and DNAm age were tested.\n\nResultsOnly delirium cases showed 3 CpGs sites in the TNF-alpha significantly correlated to age after multiple corrections. A genome-wide significant CpG site near the gene of LDLRAD4 was identified. In addition, network analysis showed several significant pathways with false discovery rate adjusted p-value < 0.05. The top pathway with GO was immune response, and the second top pathway with KEGG was cholinergic synapse. Although there was no statistically significant difference, DNAm age among non-delirium controls showed \"slower aging\" compared to delirium cases.\n\nConclusionsDNAm differences were shown both at gene and network levels between delirium cases and non-delirium controls. This finding indicates that DNAm status in blood has a potential to be used as epigenetic biomarkers for delirium.

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Saito, T., Toda, H., Duncan, G. N., Jellison, S. S., Yu, T., Klisares, M. J., Daniel, S., Andreasen, A., Leyden, L., Hellman, M., Shinozaki, E., Lee, S., Yoshino, A., Cho, H. R., Shinozaki, G.. 2019-08-08. Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients. https://doi.org/10.1101/729335

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