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

ABSTRACT: 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.

SUBMITTER: Jardine D

PROVIDER: S-EPMC4712687 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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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 D Emond Mary M Meert Kathleen L KL Harrison Rick R Carcillo Joseph A JA Anand Kanwaljeet J S KJ Berger John J Newth Christopher J L CJ Willson Douglas F DF Nicholson Carol C Dean J Michael JM Zimmerman Jerry J JJ

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 20141001 8

<h4>Objectives</h4>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.<h4>Design</h4>This was a prospective observational study employing tag single nucleotide polymorphism methodology to examine genetic contributio ...[more]

PMID: 25055195

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Project description:BackgroundCritical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.MethodsIn a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes.ResultsTotal and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons).ConclusionsDuring critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).

Project description:ObjectivesMultiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure.DesignRetrospective observational cohort study.SettingFour academic ICUs at U.S. hospitals.PatientsGenetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250).InterventionsNone.Measurements and main resultsIn discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells.ConclusionsWe found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.

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

Publications

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

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