TY - JOUR
T1 - Methylomic and transcriptomic characterization of postoperative systemic inflammatory dysregulation
AU - Bain, Chris R.
AU - Myles, Paul S.
AU - Taylor, Rachael
AU - Trahair, Hugh
AU - Lee, Yin Peng
AU - Croft, Larry
AU - Peyton, Philip J.
AU - Painter, Thomas
AU - Chan, Matthew T.V.
AU - Wallace, Sophie
AU - Corcoran, Tomás
AU - Shaw, Andrew D.
AU - Paul, Eldho
AU - Ziemann, Mark
AU - Bozaoglu, Kiymet
N1 - Funding Information:
Conflicts of interest: The authors have read the authorship agreement and policy on disclosure of potential conflicts of interest and declare that they have no conflicts. This work was primarily funded by an Australian and New Zealand College of Anaesthetists (ANZCA) research grant (15-018) and endorsed by the ANZCA Clinical Trials Network. The Victorian Cancer Biobank is supported by the Victorian Government. The RELIEF trial was funded by the Australian National Health and Medical Research Council (NHMRC). This work was also partially funded by National Health and Medical Research Council (NHMRC) Australia Project grants (GNT 1022812 and GNT 1020284). K.B is supported by an E.H. Flack Fellowship. Clinicaltrials.gov, NCT01424150, 26/8/2011. Author contributions are as follows: C.R.B. conceptualised, designed and acquired funding for the study as principal investigator. P.S.M. K.B. provided support and supervision. Chief investigators: C.R.B. A.D.S. T.C. K.B. Biobank creation, management and administration: C.R.B. R.T. H.T. K.B. RELIEF site investigators: P.P. M.T.V.C. T.P. P.S.M. Ethics: S.W. Biostatistics: E.P. DNA, RNA extraction, quality control and RNA-seq: Y.P.L. L.C. Bioinformatics: M.Z. Results analysis C.R.B. M.Z. K.B. Validation analysis: C.R.B. P.S.M. Original draft: C.R.B. P.S.M. M.Z. K.B. Data and materials availability: Analysis codes describing the above is available at https://github.com/markziemann/relief_omics. All RNA-seq and methylation array data and code have been deposited in the NCBI Gene Expression Omnibus (GEO) and are accessible through the GEO series accession number GSE184049. All other relevant data are available from the corresponding author on request. We thank Angela J. Mountain at The Victorian Cancer Biobank (Austin Hospital, Victoria Australia) and Rebekah Ward at The Cellular Therapies Laboratory (Royal Adelaide Hospital, South Australia) for blood processing and storage. We acknowledge the Australian Genome Research Facility (AGRF) for conducting the methylation assay. We acknowledge the support of the late Associate Professor Jeremy Jowett, who invited C.R.B. to join the Genomics and Systems Biology Laboratory at The Baker IDI Heart and Diabetes Institute (Melbourne, Australia), where the initial hypothesis and development for this project occurred. We acknowledge Associate Professor Christine Ball for independent editing.
Funding Information:
This work was primarily funded by an Australian and New Zealand College of Anaesthetists (ANZCA) research grant ( 15-018 ) and endorsed by the ANZCA Clinical Trials Network. The Victorian Cancer Biobank is supported by the Victorian Government. The RELIEF trial was funded by the Australian National Health and Medical Research Council (NHMRC). This work was also partially funded by National Health and Medical Research Council (NHMRC) Australia Project grants ( GNT 1022812 and GNT 1020284 ). K.B is supported by an E.H. Flack Fellowship. Clinicaltrials.gov, NCT01424150, 26/8/2011.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9
Y1 - 2022/9
N2 - In this study, we define and validate a state of postoperative systemic inflammatory dysregulation (PSID) based on postoperative phenotypic extremes of plasma C-reactive protein concentration following major abdominal surgery. PSID manifested clinically with significantly higher rates of sepsis, complications, longer hospital stays and poorer short, and long-term outcomes. We hypothesized that PSID will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression suggests that dysregulation is mediated at multiple levels within specific gene sets and hence, nonspecific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.
AB - In this study, we define and validate a state of postoperative systemic inflammatory dysregulation (PSID) based on postoperative phenotypic extremes of plasma C-reactive protein concentration following major abdominal surgery. PSID manifested clinically with significantly higher rates of sepsis, complications, longer hospital stays and poorer short, and long-term outcomes. We hypothesized that PSID will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression suggests that dysregulation is mediated at multiple levels within specific gene sets and hence, nonspecific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.
UR - http://www.scopus.com/inward/record.url?scp=85131096395&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2022.04.004
DO - 10.1016/j.trsl.2022.04.004
M3 - Article
C2 - 35470009
AN - SCOPUS:85131096395
SN - 1931-5244
VL - 247
SP - 79
EP - 98
JO - Translational Research
JF - Translational Research
ER -
