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

Gråberg,Truls; Bergman,Emma Ahlén; Strömmer,Lovisa; Sjöholm,Louise K.; Wikström,Ann-Charlotte; Winqvist,Ola; 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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1	Rettig TC, Verwijmeren L, Dijkstra IM, Boerma D, van de Garde EM and Noordzij PG: Postoperative interleukin-6 level and early detection of complications after elective major abdominal surgery. Ann Surg. 263:1207–1212. 2016. View Article : Google Scholar : PubMed/NCBI
2	Desborough JP: The stress response to trauma and surgery. Br J Anaesth. 85:109–117. 2000. View Article : Google Scholar : PubMed/NCBI
3	Barnes PJ: Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci (Lond). 94:557–572. 1998. View Article : Google Scholar : PubMed/NCBI
4	Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, Keh D, Kupfer Y, Oppert M and Meduri GU: Corticosteroids in the treatment of severe sepsis and septic shock in adults: A systematic review. JAMA. 301:2362–2375. 2009. View Article : Google Scholar : PubMed/NCBI
5	Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, et al: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American college of critical care medicine. Crit Care Med. 36:1937–1949. 2008. View Article : Google Scholar : PubMed/NCBI
6	Cain DW and Cidlowski JA: Immune regulation by glucocorticoids. Nat Rev Immunol. 17:233–247. 2017. View Article : Google Scholar : PubMed/NCBI
7	Hearing SD, Norman M, Smyth C, Foy C and Dayan CM: Wide variation in lymphocyte steroid sensitivity among healthy human volunteers. J Clin Endocrinol Metab. 84:4149–4154. 1999. View Article : Google Scholar : PubMed/NCBI
8	Graberg T, Strommer L, Hedman E, Uzunel M, Ehrenborg E and Wikstrom AC: An ex vivo RT-qPCR-based assay for human peripheral leukocyte responsiveness to glucocorticoids in surgically induced inflammation. J Inflamm Res. 8:149–160. 2015. View Article : Google Scholar : PubMed/NCBI
9	Oakley RH and Cidlowski JA: The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease. J Allergy Clin Immunol. 132:1033–1044. 2013. View Article : Google Scholar : PubMed/NCBI
10	Carvalho LA, Bergink V, Sumaski L, Wijkhuijs J, Hoogendijk WJ, Birkenhager TK and Drexhage HA: Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder. Transl Psychiatry. 4:e3442014. View Article : Google Scholar : PubMed/NCBI
11	Sanchez-Vega B, Krett N, Rosen ST and Gandhi V: Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells. Mol Cancer Ther. 5:3062–3070. 2006. View Article : Google Scholar : PubMed/NCBI
12	Turner JD and Muller CP: Structure of the glucocorticoid receptor (NR3C1) gene 5′untranslated region: Identification, and tissue distribution of multiple new human exon 1. J Mol Endocrinol. 35:283–292. 2005. View Article : Google Scholar : PubMed/NCBI
13	Turner JD, Pelascini LP, Macedo JA and Muller CP: Highly individual methylation patterns of alternative glucocorticoid receptor promoters suggest individualized epigenetic regulatory mechanisms. Nucleic Acids Res. 36:7207–7218. 2008. View Article : Google Scholar : PubMed/NCBI
14	Palma-Gudiel H, Cordova-Palomera A, Leza JC and Fananas L: Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neurosci Biobehav Rev. 55:520–535. 2015. View Article : Google Scholar : PubMed/NCBI
15	Leenen FA, Muller CP and Turner JD: DNA methylation: Conducting the orchestra from exposure to phenotype? Clin Epigenetics. 8:922016. View Article : Google Scholar : PubMed/NCBI
16	Cao-Lei L, Leija SC, Kumsta R, Wüst S, Meyer J, Turner JD and Muller CP: Transcriptional control of the human glucocorticoid receptor: Identification and analysis of alternative promoter regions. Hum Genet. 129:533–543. 2011. View Article : Google Scholar : PubMed/NCBI
17	Li-Tempel T, Larra MF, Sandt E, Mériaux SB, Schote AB, Schächinger H, Muller CP and Turner JD: The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation. Clin Epigenetics. 8:122016. View Article : Google Scholar : PubMed/NCBI
18	Suderman M, McGowan PO, Sasaki A, Huang TC, Hallett MT, Meaney MJ, Turecki G and Szyf M: Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci USA. 109 Suppl 2(Suppl 2):S17266–S17272. 2012. View Article : Google Scholar : PubMed/NCBI
19	Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S and Devlin AM: Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 3:97–106. 2008. View Article : Google Scholar : PubMed/NCBI
20	Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M and Meaney MJ: Epigenetic programming by maternal behavior. Nat Neurosci. 7:847–854. 2004. View Article : Google Scholar : PubMed/NCBI
21	Dindo D, Demartines N and Clavien PA: Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 240:205–213. 2004. View Article : Google Scholar : PubMed/NCBI
22	R Core Team (2017), . R: A language and environemnt for statistical computing. R Foundation for Statistical Computing Vienna, Austria: https://www.r-project.orgJanuary 172022
23	Bodenhofer U, Bonatesta E, Horejs-Kainrath C and Hochreiter S: msa: An R package for multiple sequence alignment. Bioinformatics. 31:3997–3999. 2015.PubMed/NCBI
24	Lê S, Josse J and Husson F: FactoMineR: An R package for multivariate analysis. Journal of Statistical Software. 25:1–18. 2008. View Article : Google Scholar
25	Mayor C, Brudno M, Schwartz JR, Poliakov A, Rubin EM, Frazer KA, Pachter LS and Dubchak I: VISTA: Visualizing global DNA sequence alignments of arbitrary length. Bioinformatics. 16:1046–1047. 2000. View Article : Google Scholar : PubMed/NCBI
26	1000 Genomes Project Consortium, . Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA and Abecasis GR: A global reference for human genetic variation. Nature. 526:68–74. 2015. View Article : Google Scholar : PubMed/NCBI
27	NHLBI GO Exome Sequencing Project (ESP), . Exome Variant Server. NHLBI; Seattle, WA: http://evs.gs.washington.edu/EVS/June 18–2018
28	Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, et al: The mutational constraint spectrum from variation in 141,456 humans. Nature. 581:434–443. 2020. View Article : Google Scholar : PubMed/NCBI
29	Howe KL, Achuthan P, Allen J, Allen J, Alvarez-Jarreta J, Amode MR, Armean IM, Azov AG, Bennett R, Bhai J, et al: Ensembl 2021. Nucleic Acids Res. 49(D1):D884–D891. 2021. View Article : Google Scholar : PubMed/NCBI
30	Sinclair D, Fullerton JM, Webster MJ and Shannon Weickert C: Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants. PLoS One. 7:e317202012. View Article : Google Scholar : PubMed/NCBI
31	Lasker MV, Leventhal SM, Lim D, Green TL, Tung K, Cho K and Greenhalgh DG: Hyperactive human glucocorticoid receptor isoforms and their implications for the stress response. Shock. 43:228–232. 2015. View Article : Google Scholar : PubMed/NCBI
32	Leventhal SM, Lim D, Green TL, Cantrell AE, Cho K and Greenhalgh DG: Uncovering a multitude of human glucocorticoid receptor variants: An expansive survey of a single gene. BMC Genet. 20:162019. View Article : Google Scholar : PubMed/NCBI
33	Baker AC, Chew VW, Green TL, Tung K, Lim D, Cho K and Greenhalgh DG: Single nucleotide polymorphisms and type of steroid impact the functional response of the human glucocorticoid receptor. J Surg Res. 180:27–34. 2013. View Article : Google Scholar : PubMed/NCBI
34	Quax RAM, Koper JW, Huisman AM, Weel A, Hazes JM, Lamberts SW and Felders RA: Polymorphisms in the glucocorticoid receptor gene and in the glucocorticoid-induced transcript 1 gene are associated with disease activity and response to glucocorticoid bridging therapy in rheumatoid arthritis. Rheumatol Int. 35:1325–1333. 2015. View Article : Google Scholar : PubMed/NCBI
35	Norden J, Pearce KF, Irving JAE, Collin MP, Wang XN, Wolff D, Kolb HJ, Socie G, Kuzmina Z, Greinix H, et al: The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation. Int J Immunogenet. 2018.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
36	Koper JW, van Rossum EFC and van den Akker EL: Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease. Steroids. 92:62–73. 2014. View Article : Google Scholar : PubMed/NCBI
37	Sherry ST, Ward M and Sirotkin K: dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res. 9:677–679. 1999. View Article : Google Scholar : PubMed/NCBI