GH deficiency status combined with GH receptor polymorphism affects response to GH in children
Armand Valsesia, Pierre Chatelain, Adam Stevens, Valentina A Peterkova, Alicia Belgorosky, Mohamad Maghnie, Franco Antoniazzi, Ekaterina Koledova, Jerome Wojcik, Pierre Farmer, Benoit Destenaves, Peter Clayton, PREDICT Investigator group, A Belgorosky, G Ambler, K Kapelari, C Deal, J Hamilton, Y Brusquet, P Chatelain, M Colle, R Coutant, S Cabrol, Y Le, R Reynaud, J-P Salles, J Weill, R Pfäffle, M Ranke, G Binder, M Bozzola, F Buzi, A Pilotta, M Cappa, A Cicognani, S Zucchini, M Maghnie, F Antoniazzi, L Tatò, D H Kim, H W Yoo, S-W Yang, E Vangsøy Hansen, D Veimo, E Bashina, Y Skorodok, V Peterkova, L Sultanova, A Carrascosa, D Yesta, A Ferrandez Longas, R Gracia Bouthellier, I Gonzalez, M D Rodriguez-Arnao, A Rodriguez-Sanchez, J P Lopez Siguero, S Quinteiro, J Dahlgren, L Hagenäs, T J Wang, J W Hou, L Bath, C Kelnar, P Clayton, Armand Valsesia, Pierre Chatelain, Adam Stevens, Valentina A Peterkova, Alicia Belgorosky, Mohamad Maghnie, Franco Antoniazzi, Ekaterina Koledova, Jerome Wojcik, Pierre Farmer, Benoit Destenaves, Peter Clayton, PREDICT Investigator group, A Belgorosky, G Ambler, K Kapelari, C Deal, J Hamilton, Y Brusquet, P Chatelain, M Colle, R Coutant, S Cabrol, Y Le, R Reynaud, J-P Salles, J Weill, R Pfäffle, M Ranke, G Binder, M Bozzola, F Buzi, A Pilotta, M Cappa, A Cicognani, S Zucchini, M Maghnie, F Antoniazzi, L Tatò, D H Kim, H W Yoo, S-W Yang, E Vangsøy Hansen, D Veimo, E Bashina, Y Skorodok, V Peterkova, L Sultanova, A Carrascosa, D Yesta, A Ferrandez Longas, R Gracia Bouthellier, I Gonzalez, M D Rodriguez-Arnao, A Rodriguez-Sanchez, J P Lopez Siguero, S Quinteiro, J Dahlgren, L Hagenäs, T J Wang, J W Hou, L Bath, C Kelnar, P Clayton
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.
© 2015 The authors.
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