ESPE Abstracts (2014) 82 P-D-1-3-165

Validating Genetic Markers of Response to Recombinant Human GH in Children with GH Deficiency or Turner Syndrome: Results From the PREDICT Validation Study

Pierre Chatelaina, Adam Stevensb, Chiara De Leonibusb, Peter Claytonb & Jerome Wojcikc

aDépartement de Pédiatrie, Université Claude Bernard, Lyon, France; bManchester Academic Health Sciences Centre, Royal Manchester Children’s Hospital, Manchester, UK; cQuartz Bio, Geneva, Switzerland

Introduction: Genetic markers associated with the response to recombinant human GH (r-hGH) have been identified in Growth Hormone Deficiency (GHD) and Turner Syndrome (TS) children in the PREDICT long-term follow-up (LTFU) prospective study (NCT00699855).1 A validation (VAL) study (NCT01419249) was conducted to confirm association.

Methods/design: Inclusion criteria for GHD and TS children were identical in the LTFU and VAL studies (GHD defined as peak GH<10 μg/l, prepubertal at start of r-hGH). The VAL patients were children who had already completed one r-hGH treatment year. Single nucleotide polymorphisms (SNPs) previously associated with GHD or TS (22 with GHD and 26 with TS) were tested. Patients (293 GHD and 132 TS) were recruited from 29 sites in nine countries. For each SNP, growth response (change in height (Ht) SDS or Ht velocity SDS) was used as the dependent variable in a regression analysis and gender, age, GH peak during provocative testing (GHD), GH dose, distance to target Ht SDS, and mid-parental Ht SDS as covariates.

Results: There were no differences in gender distribution (GHD) and SNP allele frequencies between LTFU and VAL but age, GH dose and distance to target Ht SDS were lower (P<1.2×10−5), and GH peak (GHD, P=5.8×10−5) and first year growth responses higher in VAL. Using regression modelling to control for differences in the studies and investigate interaction with covariates, we found GHD SOS1 (rs2888586) associated with change in Ht SDS with GH peak as covariate (P=0.0036 VAL; 6.4×10−5 LTFU), and in TS ESR1 SNP rs2347867 associated with Ht velocity SDS (P=0.0304 VAL; 6.2×10−6 LTFU).

Conclusions: The PREDICT validation study confirmed in an independent cohort the association of genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children, but only after controlling for covariates.

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