BioScientifica, European Journal of Endocrinology, 6(173), p. 777-789, 2015
DOI: 10.1530/eje-15-0474
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Meta-analysis has shown a modest improvement in first-year growth response to recombinant human growth hormone (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-naive pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (pGH) 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 profiles were characterized at baseline. Changes in growth (height [cm] and standard deviation score [SDS]) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on pGH 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 pGH had lower growth than subjects with fl/fl (median difference after 3 years -3.3 cm; -0.3 SDS); conversely, GHRd3 carriers with higher pGH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. Gene expression 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.