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Glucocorticoid Receptor Polymorphisms and Outcomes in Pediatric Septic Shock*

Cvijanovich, Natalie Z. MD; Anas, Nick MD; Allen, Geoffrey L. MD; Thomas, Neal J. MD; Bigham, Michael T. MD; Weiss, Scott L. MD; Fitzgerald, Julie PhD, MD; Checchia, Paul A. MD; Meyer, Keith MD; Quasney, Michael MD, PhD; Gedeit, Rainer MD; Freishtat, Robert J. MD; Nowak, Jeffrey MD; Raj, Shekhar S. MD; Gertz, Shira MD; Grunwell, Jocelyn R. MD, PhD; Opoka, Amy BS; Wong, Hector R. MD

Pediatric Critical Care Medicine: April 2017 - Volume 18 - Issue 4 - p 299–303
doi: 10.1097/PCC.0000000000001058
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Objective: Polymorphisms of the glucocorticoid receptor gene are associated with outcome and corticosteroid responsiveness among patients with inflammatory disorders. We conducted a candidate gene association study to test the hypothesis that these polymorphisms are associated with outcome and corticosteroid responsiveness among children with septic shock.

Design: We genotyped 482 children with septic shock for the presence of two glucocorticoid receptor polymorphisms (rs56149945 and rs41423247) associated with increased sensitivity and one glucocorticoid receptor polymorphism (rs6198) associated with decreased sensitivity to corticosteroids. The primary outcome variable was complicated course, defined as 28-day mortality or the persistence of two or more organ failures 7 days after a septic shock diagnosis. We used logistic regression to test for an association between corticosteroid exposure and outcome, within genotype group, and adjusted for illness severity.

Setting: Multiple PICUs in the United States.

Interventions: Standard care.

Measurements and Main Results: There were no differences in outcome when comparing the various genotype groups. Among patients homozygous for the wild-type glucocorticoid receptor allele, corticosteroids were independently associated with increased odds of complicated course (odds ratio, 2.30; 95% CI, 1.01–5.21; p = 0.047).

Conclusions: Based on these glucocorticoid receptor polymorphisms, we could not detect a beneficial effect of corticosteroids among any genotype group. Among children homozygous for the wild-type allele, corticosteroids were independently associated with increased odds of poor outcome.

1Department of Pediatrics, UCSF Benioff Children’s Hospital Oakland, Oakland, CA.

2Department of Pediatrics, Children’s Hospital of Orange County, Orange, CA.

3Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO.

4Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA.

5Department of Pediatrics, Akron Children’s Hospital, Akron, OH.

6Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA.

7Department of Pediatrics, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX.

8Department of Pediatrics, Miami Children’s Hospital, Miami, FL.

9Department of Pediatrics, C.S. Mott Children’s Hospital at the University of Michigan, Ann Arbor, MI.

10Department of Pediatrics, Children’s Hospital of Wisconsin, Milwaukee, WI.

11Department of Pediatrics, Children’s National Health System, Washington, DC.

12Department of Pediatrics, Children’s Hospital and Clinics of Minnesota, Minneapolis, MN.

13Department of Pediatrics, Riley Hospital for Children, Indianapolis, IN.

14Department of Pediatrics, Hackensack University Medical Center, Joseph M. Sanzari Children’s Hospital, Hackensack, NJ.

15Department of Pediatrics, Children’s Healthcare of Atlanta at Egleston, Atlanta, GA.

16Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and Cincinnati Children’s Research Foundation, Cincinnati, OH.

17Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

*See also p. 378.

Supported by the National Institutes of Health (NIH) (R01GM099773 and R01GM108025).

Dr. Cvijanovich received funding (per patient fee per subcontract agreement to conduct study) from Cincinnati Children’s Hospital Medical Center. Her institution received funding from Boston Children’s Hospital (per patient fee for HALFPINT NIH funded study per subcontract agreement; and per patient fee for PICFLU NIAID funded study per subcontract agreement); and from the NIH. Dr. Thomas received funding from the NIH, Therabron, and CareFusion; and his institution received funding from the U.S. Food and Drug Administration. Dr. Bigham received funding from Cincinnati Children’s Hospital, including supplies for sample collection. Dr. Weiss’s institution receiving funding from NIH (R01GM099773 and R01GM108025 paid to Dr. Wong). He also received funding from NIH (grant NIGMS K23GM110496) and ThermoFisher Scientific (honorarium for presentation unrelated to current manuscript). Dr. Meyer received funding from the Children’s Hospital of Cincinnati. Dr. Gertz received funding from Cincinnati Children’s Hospital. Drs. Allen, Fitzgerald, Checchia, Freishtat, and Wong received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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©2017The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies