Endocrine Abstracts (2008) 17 OC6

A common polymorphism of the growth hormone receptor (GHR) and response to GH: a report of 97 cases (Manchester) and literature meta-analysis

M Solomon, A Renehan, R Morjaria, L Patel, A Whatmore, G Shaikh, R Amin, I Banerjee & P Clayton

The University of Manchester, Manchester, UK.

Background: A polymorphism of the GHR gene, deletion of exon 3 (d3 GHR), has been associated with improved growth response to GH in some studies. We investigated the effect of this polymorphism across several diagnoses, evaluating parameters of growth outcome from a single institution (Manchester) and combined these with those derived from the literature using meta-analytical approaches.

Methods: GHR genotype was assessed by PCR and related to clinical and biochemical parameters from a cohort of 97 children receiving GH therapy covering a range of growth disorders. A systematic review using MEDLINE and EMBASE databases was supplemented by hand-searching conference proceedings. The primary endpoint of interest was change in height SDS (ΔHtSDS) in the first year of GH therapy. Results were combined using random-effects methods and expressed as standardized mean differences (SMD). Metaregression models were derived to test for study-level confounding factors.

Results: No significant difference in first year ΔHtSDS was observed between the GHR genotype groups in the Manchester cohort. Literature searching revealed twenty-two studies comprising 32 datasets (2402 cases). Carriage of the d3 GHR allele ranged from 16% to 61% (mean: 47%). In those studies providing ΔHtSDS in the first year of GH therapy, the summary SMD for the full length versus the d3 GHR carriers was −0.29 (95% CIs: −0.56 to −0.02, P=0.04). A metaregression model for SMD gave a P value of 0.08, indicating that the contribution of GHR genotype was weak. There was clinical heterogeneity across studies but adjustments for GH dose, mean age at start of therapy, prevalence of full length allele, and mean parental height SDS did not significantly influence the SMD metaregression model.

Conclusions: Across a range of studies covering a number of diagnoses, the evidence was weak that the GHR exon 3 genotype impacts upon ΔHtSDS in the first year of GH therapy as a primary measure of response. However, the presence of heterogeneity across clinical settings suggests that the d3 GHR allele may influence certain subgroups, and further work is required before firm conclusions can be made.