GH deficiency status combined with GH receptor polymorphism affects response to GH in children.
Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years -3.3 cm; -0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage.
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Armand
A
Valsesia
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Pierre
P
Chatelain
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Adam
A
Stevens
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Valentina A
VA
Peterkova
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Alicia
A
Belgorosky
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Mohamad
M
Maghnie
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Franco
F
Antoniazzi
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Ekaterina
E
Koledova
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Jerome
J
Wojcik
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Pierre
P
Farmer
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK.
Benoit
B
Destenaves
Merck Serono SAGeneva, SwitzerlandDépartement de PédiatrieHôpital Mère-Enfant, Université Claude Bernard, Lyon, FranceFederal State Institution 'Endocrinology Scientific Center of Russian Medical Technology'Moscow, RussiaEndocrine ServiceHospital de Pediatría Garrahan, Ciudad Autónoma de Buenos Aires, Buenos Aires, ArgentinaIRCCS Istituto Giannina Gaslini di GenovaClinica Pediatrica, Università di Genova, Genova, ItalyPediatra d.U. Azienda Ospedaliera Universitaria IntegrataUniversità di Verona, Verona, ItalyManchester Academic Health Sciences CentreRoyal Manchester Children's Hospital, 5th Floor, Oxford Road, Manchester M13 9WL, UK peter.clayton@manchester.ac.uk.
Peter
P
Clayton
D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D001786:Blood Glucose / Q000378:metabolism; D001827:Body Height; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D004393:Dwarfism, Pituitary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005091:Exons; D020869:Gene Expression Profiling; D006130:Growth Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019382:Human Growth Hormone / Q000172:deficiency / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008137:Longitudinal Studies; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011986:Receptors, Somatotropin / Q000235:genetics; D011994:Recombinant Proteins; D012720:Severity of Illness Index; D013972:Thyrotropin / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism; D016896:Treatment Outcome; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019382:Human Growth Hormone; C583557:IGF1 protein, human; C515497:IGFBP3 protein, human; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D013972:Thyrotropin; D013974:Thyroxine; D014280:Triglycerides