title: Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome.
abstract: Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) (n=166) or Turner syndrome (TS) (n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I (P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS (r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose.
authors.affiliation: Manchester Academic Health Sciences Centre, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Stevens
authors.affiliation: Manchester Academic Health Sciences Centre, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Clayton
authors.affiliation: Clinica Pediatrica, Università degli Studi di Verona, Verona, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Tatò
authors.affiliation: Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Yoo
authors.affiliation: Paediatric Endocrine Unit, Hospital General Universitario Gregorio Marañón and Universidad Complutense, Madrid, Spain.
authors.forename: M D
authors.initials: MD
authors.lastname: Rodriguez-Arnao
authors.affiliation: St Petersburg State Pediatric Medical Academy, Department of Endocrinology, St Petersburg, Russia.
authors.forename: J
authors.initials: J
authors.lastname: Skorodok
authors.affiliation: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: G R
authors.initials: GR
authors.lastname: Ambler
authors.affiliation: Merck Serono S.A.-Geneva, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Zignani
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Zieschang
authors.affiliation: Merck Serono S.A.-Geneva, Geneva, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Della Corte
authors.affiliation: Merck Serono S.A.-Geneva, Geneva, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Destenaves
authors.affiliation: Merck Serono S.A.-Geneva, Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Champigneulle
authors.affiliation: Genizon Biosciences, St Laurent, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Raelson
authors.affiliation: Department Pediatrie, Service d'Endocrinologie & Diabétologie Pédiatriques, Hôpital Mère-Enfant-Université Claude Bernard, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Chatelain
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006130:Growth Disorders / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000172:deficiency* / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011994:Recombinant Proteins; D059467:Transcriptome; D014424:Turner Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics
chemical_list: D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4