Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications

Gråberg,Truls; Gråberg,Truls; Bergman,Emma Ahlén; Bergman,Emma Ahlén; Strömmer,Lovisa; Strömmer,Lovisa; Sjöholm,Louise K.; Sjöholm,Louise K.; Wikström,Ann-Charlotte; Wikström,Ann-Charlotte; Winqvist,Ola; Winqvist,Ola; Winerdal,Max; Winerdal,Max

doi:10.3892/mmr.2022.12714

Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications

Authors:
- Truls Gråberg
- Emma Ahlén Bergman
- Lovisa Strömmer
- Louise K. Sjöholm
- Ann-Charlotte Wikström
- Ola Winqvist
- Max Winerdal
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Affiliations: Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institute, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, Department of Medicine, Immunology and Allergy Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital Solna, 17176 Stockholm, Sweden, Department of Clinical Immunology and Transfusion Medicine, Karolinska University Laboratory, Karolinska Institute, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden, ABClabs, BioClinicum, 17176 Stockholm, Sweden
Published online on: April 21, 2022 https://doi.org/10.3892/mmr.2022.12714
Article Number: 198
Copyright: © Gråberg et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Patients undergoing major surgery experience postoperative inflammation, which may contribute to postoperative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome and specifically postoperative inflammation. Exon 1 of the NR3C1 gene, encoding the GC receptor (GR), contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. The present study investigated the methylation status and genotype in the cytosine‑phosphate‑guanine (CpG) island in exon 1 of NR3C1 in 24 patients [Median age 65.5 (range 42‑81) years, 11 male, 13 female] who underwent major abdominal (12 pancreatic, 12 hepatic) surgery and explored its association with postoperative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien‑Dindo classification and 14 out of 24 patients had postoperative complications. Multifactorial and partial least square analyses were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with postoperative complications. Four SNPs were significantly associated with higher Clavien‑Dindo scores. Genetic variability in the chromosome 5:143,402,505‑143,405,805 region of exon 1 of the GR gene NR3C1, but not DNA methylation, was associated with more severe postoperative complications in patients having major abdominal surgery. These results indicated that the patients' response to GCs may be of clinical importance for inflammatory conditions.

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