Session: FP20-Growth: Clinical Trials & Observational Studies
Room 122 (Moscone Center)
Poster Board SUN-630
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
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