Abstract
ObjectiveSingle-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations.Design and methodsChildren with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification.ResultsThe children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes – SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR).ConclusionsThe PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use.
Highlights
The demographics and baseline clinical data for the children included in the PREDICT long-term follow-up (LTFU) study differed from those included in the VAL study
Distance below target height SDS was greater in the VAL study in growth hormone deficiency (GHD) (P ≤ 2 × 10−9) and GH dose was lower in the VAL study (GHD: P ≤ 4 × 10−21, Turner syndrome (TS): P ≤ 6 × 10−4) (Table 1)
This study was designed to validate the SNPs identified within the original PREDICT LTFU study as being associated with response to recombinant human growth hormone (r-hGH) therapy in children with either GHD or TS
Summary
Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study. Adam Stevens[1], Philip Murray[1], Jerome Wojcik[2], John Raelson[3], Ekaterina Koledova[4], Pierre Chatelain[5], Peter Clayton[1] and The PREDICT Investigator Group†. Correspondence should be addressed to P Clayton Email peter.clayton@manchester. Correspondence should be addressed to P Clayton Email peter.clayton@manchester. ac.uk
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