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Glucocorticoid Receptor Polymorphisms in Children Undergoing Congenital Heart Surgery with Cardiopulmonary Bypass
Saul Flores1,2, Ilias Iliopoulos3, Rohit S Loomba4
1Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States.
Insights
Gene variations influence corticosteroid response in children after congenital heart surgery. Specific polymorphisms affected outcomes like transcriptional intermediary factor (TIF) and low cardiac output scores (LCOS).
Area of Science:
- Genetics and Genomics
- Pediatric Cardiology
- Pharmacogenomics
Background:
- Corticosteroids are used in pediatric congenital heart surgery but their effectiveness varies.
- Genetic factors may influence individual responses to corticosteroids.
- Understanding these genetic associations can optimize patient outcomes.
Purpose of the Study:
- To investigate the association between specific gene polymorphisms and corticosteroid responsiveness in children undergoing congenital heart surgery.
- To determine if these polymorphisms correlate with clinical outcomes such as duration of inotropic support, low cardiac output scores (LCOS), and vasoactive inotrope scores.
- To explore the impact of genetic variations on transcriptional intermediary factor (TIF).
Main Methods:
- Prospective observational cohort study at a pediatric cardiac center.
- Enrolled 83 children undergoing congenital heart surgery.
- Analyzed three gene polymorphisms: N363 and 9β (increased corticosteroid sensitivity), and Bcl I (decreased sensitivity).
- Utilized Kaplan-Meier analysis and multivariable Cox regression to assess outcomes.
Main Results:
- Heterozygous N363 polymorphism was linked to longer TIF (p=0.05).
- Heterozygous 9β polymorphism was associated with shorter TIF (HR=2.04, p=0.03) and lower LCOS (p=0.01).
- Increased corticosteroid sensitivity polymorphisms correlated with longer TIF, while decreased sensitivity polymorphisms correlated with shorter TIF.
Conclusions:
- Gene polymorphisms significantly influence corticosteroid responsiveness and clinical outcomes in pediatric congenital heart surgery patients.
- The 9β polymorphism shows a notable association with both TIF and LCOS.
- Pharmacogenetic insights are crucial for tailoring corticosteroid therapy in this population.
Abstract:
We conducted a candidate gene association study to test the hypothesis that different gene polymorphisms will be associated with corticosteroid responsiveness and study outcomes among children undergoing congenital heart surgery. This is a prospective observational cohort study at a large, tertiary pediatric cardiac center on children undergoing corrective or palliative congenital heart surgery. A total of 83 children were enrolled. DNA was isolated for three polymorphisms of interest namely N363 (rs56149945) and 9β (rs6198) associated with increased sensitivity to corticosteroids and Bcl I (rs41423247) associated with decreased sensitivity to corticosteroids. Duration of inotropic use, low cardiac output scores (LCOS), and vasoactive inotrope scores were examined in relation to these three polymorphisms. Using Kaplan-Meier analysis, heterozygous individuals showed longer transcriptional intermediary factor (TIF) compared with wild type for N363 polymorphism ( p = 0.05). In multivariable Cox regression, heterozygous alleles for 9β polymorphism showed significantly shorter TIF compared with wild type (hazard ratio = 2.04 [1.08-3.87], p = 0.03). The relationship between lower LCOS scores and alleles groups was significant for 9β heterozygous polymorphism only (1.5 [1-2.2], p = 0.01) in comparison to wild type and homozygous. The presence of heterozygote alleles for the increased corticosteroid sensitivity is associated with longer TIF compared with wild type. Conversely, the presence of heterozygous alleles for the decreased sensitivity to corticosteroids is associated with shorter TIF compared with wild type.
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