title: A single nucleotide polymorphism in the corticotropin receptor gene is associated with a blunted cortisol response during pediatric critical illness.
abstract: OBJECTIVE
  The cortisol response during critical illness varies widely among patients. Our objective was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the cortisol response among critically ill children.
  
  
  METHODS
  This was a prospective observational study employing tag single nucleotide polymorphism methodology to examine genetic contributions to the variability of the cortisol response in critical illness. Thirty-one candidate genes and 31 ancestry markers were examined.
  
  
  METHODS
  Patients were enrolled from seven pediatric critical care units that constitute the Eunice Kennedy Shriver Collaborative Pediatric Critical Care Research Network.
  
  
  METHODS
  Critically ill children (n = 92), age 40 weeks gestation to 18 years old, were enrolled.
  
  
  METHODS
  Blood samples were obtained from all patients for serum cortisol measurements and DNA isolation. Demographic and illness severity data were collected.
  
  
  RESULTS
  Single nucleotide polymorphisms were tested for association with serum free cortisol concentrations in context of higher illness severity as quantified by Pediatric Risk of Mortality III score greater than 7. A single nucleotide polymorphism (rs1941088) in the MC2R gene was strongly associated (p = 0.0005) with a low free cortisol response to critical illness. Patients with the AA genotype were over seven times more likely to have a low free cortisol response to critical illness than those with a GG genotype. Patients with the GA genotype exhibited an intermediate free cortisol response to critical illness.
  
  
  CONCLUSIONS
  The A allele at rs1941088 in the MC2R gene, which encodes the adrenocorticotropic hormone (corticotropin, ACTH) receptor, is associated with a low cortisol response in critically ill children. These data provide evidence for a genetic basis for a portion of the variability in cortisol production during critical illness. Independent replication of these findings will be important and could facilitate development of personalized treatment for patients with a low cortisol response to severe illness.
authors: 1Department of Anesthesiology, University of Washington School of Medicine, Seattle, WA. 2Department of Biostatistics, University of Washington School of Medicine, Seattle, WA. 3Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI. 4Department of Pediatrics, University of California at Los Angeles, Los Angeles, CA. 5Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA. 6Department of Pediatrics, Le Bonheur Children's Hospital and University of Tennessee Health Science Center, Memphis, TN. 7Department of Pediatrics, Children's National Medical Center, Washington, DC. 8Department of Anesthesiology and Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, CA. 9Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, VA. 10Eunice Kennedy Shriver, National Institute of Child Health and Human Development, Washington, D.C. 11Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT. 12Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.
authors: David
authors: D
authors: Jardine
authors: Mary
authors: M
authors: Emond
authors: Kathleen L
authors: KL
authors: Meert
authors: Rick
authors: R
authors: Harrison
authors: Joseph A
authors: JA
authors: Carcillo
authors: Kanwaljeet J S
authors: KJ
authors: Anand
authors: John
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authors: Berger
authors: Christopher J L
authors: CJ
authors: Newth
authors: Douglas F
authors: DF
authors: Willson
authors: Carol
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authors: Nicholson
authors: J Michael
authors: JM
authors: Dean
authors: Jerry J
authors: JJ
authors: Zimmerman
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness / Q000628:therapy; D004247:DNA / Q000032:analysis; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis / Q000097:blood*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000305:Adrenal Cortex Hormones; C561839:NR3C2 protein, human; D044103:Receptor, Melanocortin, Type 2; D018161:Receptors, Mineralocorticoid; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D006854:Hydrocortisone