Farmer, Pierre, Valsesia, Armand, Chatelain, Pierre and Clayton, Peter (2015) GH deficiency status combined with GH receptor polymorphism affects response to GH in children. European Journal of Endocrinology, 173 (6). pp. 777-789. ISSN 1479-683X

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-naı¨ve 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 mg/l (severe GHD; nZ45) andO4 to!10 mg/l mild GHD; nZ49) 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 K3.3 cm; K0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (C2.7 cm; C0.2 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.

Item Type:	Article
Keywords:	GH deficiency, GH receptor polymorphism, GHRd3, pharmacogenomics
Date Deposited:	13 Jun 2016 23:45
Last Modified:	13 Jun 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27653