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A Single Nucleotide Polymorphism in the Corticotropin Receptor Gene Is Associated With a Blunted Cortisol Response During Pediatric Critical Illness*

Jardine, David MD1; Emond, Mary PhD2; Meert, Kathleen L. MD3; Harrison, Rick MD4; Carcillo, Joseph A. MD5; Anand, Kanwaljeet J. S. MBBS, DPhil6; Berger, John MD7; Newth, Christopher J. L. MD, FRCPC8; Willson, Douglas F. MD9; Nicholson, Carol MD10; Dean, J. Michael MD11; Zimmerman, Jerry J. MD, PhD12; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network

Pediatric Critical Care Medicine: October 2014 - Volume 15 - Issue 8 - p 698–705
doi: 10.1097/PCC.0000000000000193
Feature Articles

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.

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.

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

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.

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.

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.

* See also p. 769.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal).

This work was supported, in part, by cooperative agreements (U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, and U01HD049934) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Department of Health and Human Services, as well as a Recovery Act Administrative Supplement 3U10HD049945-05S1.

Dr. Zimmerman served as board member for the Council of the Society of Critical Care Money (reimbursement for travel); is employed by the Seattle Children’s Hospital, Children’s University Medical Group, and the University of Washington; received royalties from Elsevier Publishing (Co-editor royalties for Pediatric Critical Care); and received support for article research from the National Institutes of Health (NIH). His institution received grant support from the NIH 3U10HD049945-05S1 and the NIH 1R01HD073362-01A1. Dr. Jardine received support for article research from the NIH. His institution received grant support, support for travel, and support for participation in review activities. Dr. Emond received support for article research from the NIH. Her institution received grant support. Dr. Meert received support for article research from the NIH. Her institution received grant support from the NICHD. Dr. Harrison received support for article research from the NIH. His institution received grant support from the NIH (CPCCRN grant). Dr. Carcillo received support for article research from the NIH and disclosed other support from the NICHD – CPCCRN. His institution received grant support and support for travel from the NICHD. Dr. Anand consulted for AstraZeneca, received royalties from Up-To-Date Website, received support for article research from the NIH, and disclosed government work. His institution received grant support and support for travel from the NICHD. Dr. Berger received support for article research from the NIH. His institution received grant support from the NIH and the Association of Pediatric Pulmonary Hypertension. Dr. Newth consulted for Philips Medical and received support for article research from the NIH. His institution received grant support from the NIH / NICHD (Collaborative Pediatric Critical Care Research Network (CPCCRN) and Nellcor. Dr. Nicholson disclosed government work and received support for article research from the NIH (He was the Project Scientist for the CPCCRN during the study, assisted in its design, and implemented funding for the project). Dr. Dean received support for article research from the NIH. His institution received grant support from the NIH. Dr. Willson disclosed that he does not have any potential conflicts of interest.

For information regarding this article, E-mail: dsj@u.washington.edu

©2014The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies