A pharmacogenomic approach to the treatment of children with GH deficiency or Turner syndrome

Abstract

Objective: Individual sensitivity to recombinant human GH (r-hGH) is variable. Identification of genetic factors contributing to this variability has potential use for individualization of treatment. The objective of this study was to identify genetic markers and gene expression profiles associated with growth response on r-hGH therapy in treatment-naïve, prepubertal children with GH deficiency (GHD) or Turner syndrome (TS).

Design: A prospective, multicenter, international, open-label pharmacogenomic study.

Methods: The associations of genotypes in 103 growth- and metabolism-related genes and baseline gene expression profiles with growth response to r-hGH (cm/year) over the first year were evaluated. Genotype associations were assessed with growth response as a continuous variable and as a categorical variable divided into quartiles.

Results: Eleven genes in GHD and ten in TS, with two overlapping between conditions, were significantly associated with growth response either as a continuous variable (seven in GHD, two in TS) or as a categorical variable (four more in GHD, eight more in TS). For example, in GHD, GRB10 was associated with high response (≥ Q3; P=0.0012), while SOS2 was associated with low response (≤ Q1; P=0.006), while in TS, LHX4 was associated with high response (P=0.0003) and PTPN1 with low response (P=0.0037). Differences in expression were identified for one of the growth response-associated genes in GHD (AKT1) and for two in TS (KRAS and MYOD1).

Conclusions: Carriage of specific growth-related genetic markers is associated with growth response in GHD and TS. These findings indicate that pharmacogenomics could have a role in individualized management of childhood growth disorders.

Trial registration: ClinicalTrials.gov NCT00699855.

Figures

Figure 1

(A and C) The first and second principal components (PCs), based on a PC analysis undertaken on Tag single nucleotide polymorphisms for children with (A) GH deficiency (GHD) and (C) Turner syndrome (TS). The first PC clearly demarcates children from Asian countries vs children from all other countries. (B and D) The relationship between first-year growth response and the first PC in children with (B) GHD and (D) TS. There is complete overlap in growth response between children from Asian countries vs children from all other countries. The same overlap occurs with the second PC (data not shown). Countries are Argentina, Australia, Austria, Canada, France, Germany, Italy, Korea, Norway, Russia, Spain, Sweden, Taiwan and UK.

Figure 2

‘Heat map’ of genes associated with first-year growth response to r-hGH in (A) children with GH deficiency (GHD) and (B) girls with Turner syndrome (TS). Each column (x-axis) represents an individual child (with growth rate (cm) shown), and each row (y-axis) represents an individual gene. Red color in a cell indicates increased gene expression and green color in a cell represents decreased gene expression in the lowest quartile vs the rest. The box indicates the expression profiles of those in the lowest quartile. The ‘dendrogram’, which groups ‘clusters’ of genes with similar expression levels, is shown on the left side of each figure. Low Q, lowest quartile (≤Q1).

Figure 3

Biologic networks inferred from genes associated with growth response in children with (A) GH deficiency (GHD) and (B) Turner syndrome (TS). Blue shading indicates genes found to be associated with growth response in this study; orange shading indicates genes within the network associated with differences in baseline expression; orange/blue shading represents putative eQTLs, where there is both a genetic association and a change in gene expression; white shading represents genes in the inferred network, which have not been directly associated with growth response or gene expression difference. The tables show gene expression differences when comparing low growth response (quartile, Q1 vs Q2–Q4) and high growth response (quartile, Q4 vs Q1–Q3); green cells of the table represent downregulated gene expression; red cells of the table represent upregulated gene expression and gray cells of the table represent no change in gene expression.