title: Genetic variation of TLR4 influences immunoendocrine stress response: an observational study in cardiac surgical patients.
abstract: BACKGROUND
  Systemic inflammation (for example, following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum.
  
  
  METHODS
  A total of 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and granulocyte macrophage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day.
  
  
  RESULTS
  Thirteen patients were identified as TLR2 SNP carriers, 51 as TLR4 SNP carriers and 274 patients as non-carriers. Basal levels of ACTH, cortisol and cytokines did not differ among groups. In all three groups a significant, transient perioperative rise of cortisol could be observed. However, only in the non-carrier group this was accompanied by a significant ACTH rise. TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers (mean (95% confidence intervals)) non-carriers: 201.9 (187.7 to 216.1) pg/ml; TLR4 SNP carriers: 149.9 (118.4 to 181.5) pg/ml; TLR2 SNP carriers: 176.4 ((110.5 to 242.3) pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks (mean (95% confidence intervals)): IL-8: non-carriers: 42.6 (36.7 to 48.5) pg/ml, TLR4 SNP carriers: 23.7 (10.7 to 36.8) pg/ml; IL-10: non-carriers: 83.8 (70.3 to 97.4) pg/ml, TLR4 SNP carriers: 54.2 (24.1 to 84.2) pg/ml; GM-CSF: non-carriers: 33.0 (27.8 to 38.3) pg/ml, TLR4 SNP carriers: 20.2 (8.6 to 31.8) pg/ml). No significant changes over time or between the groups were found for the other cytokines.
  
  
  CONCLUSIONS
  Regulation of the immunoendocrine stress response during systemic inflammation is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this genotype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (for example, adrenal insufficiency) during systemic inflammation and sepsis.
authors.affiliation: Clinic of Anaesthesiology, Intensive Care Medicine and Pain Therapy, JW-Goethe-University Hospital, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. a.koch@med.uni-frankfurt.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Lutz
authors.initials: L
authors.lastname: Hamann
authors.forename: Matthias
authors.initials: M
authors.lastname: Schott
authors.forename: Olaf
authors.initials: O
authors.lastname: Boehm
authors.forename: Dirk
authors.initials: D
authors.lastname: Grotemeyer
authors.forename: Muhammed
authors.initials: M
authors.lastname: Kurt
authors.forename: Carsten
authors.initials: C
authors.lastname: Schwenke
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000368:Aged; D006348:Cardiac Surgical Procedures; D005260:Female; D005838:Genotype; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D016753:Interleukin-10 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D059035:Perioperative Period; D010913:Pituitary-Adrenal System / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013312:Stress, Physiological / Q000235:genetics; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D016209:Interleukin-8; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000324:Adrenocorticotropic Hormone