GH deficiency status combined with GH receptor polymorphism affects response to GH in children

Armand Valsesia,Jerome Wojcik,Mohamad Maghnie,Alicia Belgorosky,Benoit Destenaves,Pierre Chatelain,Ekaterina Koledova,Franco Antoniazzi,Pierre Farmer,Peter Clayton,Adam Stevens,Valentina A Peterkova

doi:10.1530/eje-15-0474

Abstract

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.

Highlights

Response to growth hormone (GH) therapy is variable in subjects who are GH-deficient [1]
No significant differences in baseline characteristics were found between subjects with the fl/fl genotype and d3 carriers when assessed by GH deficiency (GHD) severity group (Supplementary Table 1)
The cohort was recruited from growth centers across the world, and purposely included children whose diagnosis of GHD was based on local criteria along with a peak GH level !10 mg/l in two stimulation tests

Summary

Introduction

Response to growth hormone (GH) therapy is variable in subjects who are GH-deficient [1]. BMI, and gender have a role in this individual variability, while genetic factors influencing response to GH are actively being investigated. Confounding factors, such as severity of GHD, may explain conflicting data between studies

Methods

Results

Conclusion