FP20-2 Severity of Growth Hormone (GH) Deficiency (GHD) Influences the Impact of the Exon 3-Deleted GH Receptor Polymorphism on Response to GH Therapy in Children with GHD

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP20-Growth: Clinical Trials & Observational Studies
Clinical
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:50 AM
Room 122 (Moscone Center)

Poster Board SUN-630
Armand Valsesia1, Peter Ellis Clayton2, Benoit Destenaves3, Pierre Farmer1, Adam Stevens4, Cheri Deal5, Alicia Belgorosky6, Han-Wook Yoo7 and Pierre Chatelain*8
1Merck Serono, Geneva, Switzerland, 2Royal Manchester Children's Hospital, Manchester, United Kingdom, 3Merck Serono S.A., Geneva, Switzerland, 4University of Manchester, Manchester, United Kingdom, 5CHU-Sainte Justine and University of Montreal, Montreal, Canada, 6Hospital de Pediatria Garrahan, Buenos Aires, Argentina, 7Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, 8Universite Claude Bernard, Lyon, France
BACKGROUND: The exon 3-deleted GH receptor (GHRd3) polymorphism was the first genetic variant shown to influence response to recombinant-human (r-h)GH. Meta-analysis showed a modest improvement in first year growth response for GHRd3 carriers, but with significant inter-study variability. GHD severity could act as a confounder.

OBJECTIVE: To investigate associations between the presence of GHRd3, 1mth change in GH-related serum biomarkers, and growth response to r-hGH over 3yrs in relation to GHD severity in treatment-naive prepubertal children with GHD.

METHODS: Children with GHD (n=125) were enrolled from the PREDICT (NCT00256126; serum biomarker responses to r-hGH over 1mth) and PREDICT long-term follow-up (NCT00699855; annual growth responses to r-hGH) studies. Children were categorized according to peak GH level during a provocation test: ≤4µg/L (lower; n=45) and >4 to <10µg/L (higher; n=49); all children were genotyped for the GHRd3 polymorphism (full length [fl/fl], fl/d3, d3/d3). The mean r-hGH dose through the study was 33µg/kg/d with no differences between subgroups. Growth response variables (change in height [cm and standard deviation score (SDS)]) and biomarker changes over 1mth (insulin-like growth factor [IGF]-I and IGF-binding protein-3, low-density lipoprotein [LDL]-cholesterol, triglyceride [TG], and free [f] T4) were tested for association with GHRd3 (linear mixed effects models; peak GH as a fixed effect).

RESULTS: 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 were associated with height change over 3yrs (p-values <0.05): GHRd3 carriers with lower peak GH had lower growth than fl/fl carriers (median difference after 1yr –1.0 cm; –0.13 SDS); conversely, GHRd3 carriers with higher peak GH had better growth than fl/fl carriers (+1.2 cm; +0.14 SDS). Similar relationships were found for biomarker changes: GHRd3 carriers with lower peak GH had smaller increases in IGF-I (consistent with poorer growth) and TG, and smaller decreases in LDL-cholesterol and fT4 vs fl/fl carriers; the opposite was found for GHRd3 carriers with higher peak GH.

CONCLUSIONS: Data show that responses to r-hGH depend on interaction between GHD severity and GHRd3 carriage; this may explain published discrepancies on the impact of GHRd3 and emphasizes the need to control for baseline characteristics in pharmacogenomic studies.

Disclosure: AV: Employee, Merck Serono. PEC: Speaker, Merck Serono, Investigator, Merck Serono. BD: Employee, Merck Serono. PF: Employee, Merck Serono. AS: Speaker, Merck Serono. CD: Investigator, EMD Serono, Speaker, EMD Serono, Consultant, EMD Serono, Investigator, Merck Serono, Speaker, Merck Serono, Consultant, Merck Serono. HWY: Speaker, Merck Serono. PC: Consultant, Merck Serono, Speaker, Merck Serono, Investigator, Merck Serono. Nothing to Disclose: AB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study was supported by Merck Serono S.A. Geneva, Switzerland, a branch of Merck Serono S.A. Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.