title: Genetic and in vivo determinants of glucocorticoid sensitivity in relation to clinical outcome of childhood nephrotic syndrome.
abstract: Following initial glucocorticoid treatment, the clinical course in children with nephrotic syndrome is highly variable. Intrinsic sensitivity to glucocorticoids might be a determinant of this variability. Functional polymorphisms of the glucocorticoid receptor gene NR3C1 have been associated with either relatively impaired (GR-9β) or increased (BclI) glucocorticoid sensitivity. Here, in a prospective, well-defined cohort of children with nephrotic syndrome, we evaluated both carriage of GR-9β+TthIII-1 and BclI haplotypes in 113 children and a dexamethasone suppression test in 90 children in relation to their clinical outcome over a median follow-up of 4.4 years. Carriers of GR-9β+TthIII-1 had a significantly higher incidence of steroid dependence 13/25 (52%) compared with noncarriers 19/75 (25%) with a hazard ratio adjusted for gender, age, and descent of 3.04 with 95% confidence interval 1.37-6.74. Both first and frequent relapses happened significantly more often in GR-9β+TthIII-1 carriers than in noncarriers. There were no significant differences in therapeutic outcomes between carriers and noncarriers of the BclI haplotype. Results of the dexamethasone test showed no associations with clinical outcome. Thus, the GR-9β+TthIII-1 haplotype of the glucocorticoid receptor gene offers new insights into the clinical course of children with nephrotic syndrome.
authors.affiliation: Division of Nephrology, Department of Pediatrics, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Teeninga
authors.affiliation: Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Joana E
authors.initials: JE
authors.lastname: Kist-van Holthe
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Erica L T
authors.initials: EL
authors.lastname: van den Akker
authors.affiliation: Division of Nephrology, Department of Pediatrics, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Kersten
authors.affiliation: Division of Epidemiology, Department of Cardiology, Thorax Centre, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Boersma
authors.affiliation: Department of Clinical Chemistry, Medlon, MST Hospital, Enschede, The Netherlands.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Krabbe
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Division of Nephrology, Department of Pediatrics, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Heijden
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Koper
authors.affiliation: Division of Nephrology, Department of Pediatrics, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Nauta
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use*; D006239:Haplotypes; D006801:Humans; D008297:Male; D009404:Nephrotic Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D009426:Netherlands; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000235:genetics*; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D011239:Prednisolone