Glucocorticoid Receptor Polymorphisms and Outcomes in Pediatric Septic Shock.
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.


METHODS
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.


METHODS
Multiple PICUs in the United States.


METHODS
Standard care.


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.
Natalie Z
NZ
Cvijanovich
Nick
N
Anas
Geoffrey L
GL
Allen
Neal J
NJ
Thomas
Michael T
MT
Bigham
Scott L
SL
Weiss
Julie
J
Fitzgerald
Paul A
PA
Checchia
Keith
K
Meyer
Michael
M
Quasney
Rainer
R
Gedeit
Robert J
RJ
Freishtat
Jeffrey
J
Nowak
Shekhar S
SS
Raj
Shira
S
Gertz
Jocelyn R
JR
Grunwell
Amy
A
Opoka
Hector R
HR
Wong
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D016905:Gram-Negative Bacterial Infections / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016908:Gram-Positive Bacterial Infections / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012772:Shock, Septic / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005819:Genetic Markers; D011965:Receptors, Glucocorticoid