A single nucleotide polymorphism in the corticotropin receptor gene is associated with a blunted cortisol response during pediatric critical illness

David Jardine, Mary Emond, Kathleen L. Meert, Rick Harrison, Joseph A. Carcillo, Kanwaljeet J.S. Anand, John Berger, Christopher J.L. Newth, Douglas F. Willson, Carol Nicholson, J. Michael Dean, Jerry J. Zimmerman

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Interventions: Blood samples were obtained from all patients for serum cortisol measurements and DNA isolation. Demographic and illness severity data were collected.

Design: 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.

Setting: Patients were enrolled from seven pediatric critical care units that constitute the Eunice Kennedy Shriver Collaborative Pediatric Critical Care Research Network. Subjects: Critically ill children (n = 92), age 40 weeks gestation to 18 years old, were enrolled.

Measurements and Main 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.

Objectives: 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.

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. (Pediatr Crit Care Med 2014; 15:698-705).

Original languageEnglish
Pages (from-to)698-705
Number of pages8
JournalPediatric Critical Care Medicine
Volume15
Issue number8
DOIs
StatePublished - Oct 10 2014

Keywords

  • Acth) receptor
  • Adrenocorticotropin hormone (corticotropin
  • Critical illness
  • Pediatric risk of mortality iii
  • Serum free cortisol
  • Single nucleotide polymorphism
  • Single nucleotide variant
  • Stress response

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