title: Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.
abstract: OBJECTIVE
  Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations.
  
  
  METHODS
  Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification.
  
  
  RESULTS
  The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes - SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR).
  
  
  CONCLUSIONS
  The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use.
authors.affiliation: Faculty of BiologyMedicine and Health, University of Manchester and Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Stevens
authors.affiliation: Faculty of BiologyMedicine and Health, University of Manchester and Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Murray
authors.affiliation: Quartz BioGeneva, Switzerland.
authors.forename: Jerome
authors.initials: J
authors.lastname: Wojcik
authors.affiliation: Genizon BioSciencesSt Laurent, Quebec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Raelson
authors.affiliation: Merck KGaADarmstadt, Germany.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Koledova
authors.affiliation: Department PediatrieHôpital Mère-Enfant - Université Claude Bernard, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chatelain
authors.affiliation: Faculty of BiologyMedicine and Health, University of Manchester and Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK peter.clayton@manchester.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004393:Dwarfism, Pituitary / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics*; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D016896:Treatment Outcome; D014424:Turner Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D011994:Recombinant Proteins; D019382:Human Growth Hormone