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Common Polymorphisms of the Growth Hormone (GH) Receptor Do Not Correlate with the Growth Response to Exogenous Recombinant Human GH in GH-Deficient Children

Department of Pediatrics (A.P., M.F., B.F., E.P., L.D.N., F.B.), Institute of Molecular Medicine A. Nocivelli (P.M.), and Section of Medical Statistics (G.P.), University of Brescia, 25123 Brescia, Italy

Address all correspondence and requests for reprints to: Dr. F. Buzi, Clinica Pediatrica dell’Università di Brescia, P.le Spedali Civili 1, 25123 Brescia, Italy. E-mail: fbuzi{at}med.unibs.it.

	Abstract

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Context: GH acts through the GH receptor (GHR), whose polymorphisms might affect the growth response to recombinant human GH (rhGH).

Objective: The objective of this study was to investigate possible influences of GHR polymorphisms on the growth response to rhGH in GH-deficient (GHD) children.

Design: This was a 2-yr study (first year, spontaneous growth; second year, growth during rhGH treatment).

Setting: This study was performed at a referral center.

Patients: Fifty-four prepubertal GHD children (11 females; mean age, 7.8 yr; SD, 3.96) were studied.

Intervention: Patients were treated with rhGH (0.2 mg/kg·wk) for at least 1 yr after diagnosis. Growth velocity (GV) was measured 1 yr before treatment and during the first treatment year. GHR exons were amplified by PCR using pairs of intronic primers. The presence of single or multiple mismatches in the PCR products was revealed by denaturing high-pressure liquid chromatography. For exons in which mismatches were found by denaturing high-pressure liquid chromatography, direct sequencing was performed by automatic sequencer.

Main Outcome Measures: Before the start of treatment, the mean height (Ht) SD score was –1.93 (SD, 0.70), and the mean GV SD score was –1.49 (SD, 1.26).

Results: The posttreatment (first 12 months) mean GV SD score was 3.55 (SD, 3.27). Molecular analysis revealed a high frequency of GHR polymorphisms; in particular: exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 in 44 (82%), and polymorphism 1576 A>C at codon 526 of exon 10 in 35 (65%). In most patients, these different polymorphisms recurred in association. We found no significant differences in GV between the groups of subjects defined by the polymorphic genotypes.

Conclusion: The most common GHR polymorphisms, alone or in association, do not appear to affect the growth response to rhGH in GHD children.

	Introduction

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THE GROWTH RESPONSE to exogenous GH in GH-deficient (GHD) subjects varies substantially between individuals. Variables affecting the growth response to GH include age and height deficit at treatment start, severity and duration of GH deficiency (GHD), GH dose regimen, and treatment duration; furthermore, different degrees of peripheral sensitivity to GH have been hypothesized (1).

GH acts at the target cell through the GH receptor (GHR) (2, 3). After binding to GHR, GH stimulates a cascade of events that leads to target gene transcription (4). Defects in the GHR gene are responsible for Laron syndrome (5, 6) and have also been described in subjects with idiopathic short stature (ISS) (7, 8, 9). Polymorphisms of the GHR (GHRP) have been reported in the general population and have been described in exons 3, 6, and 10 (10). Because GH acts through the GHR, it is conceivable that GHRPs might affect the growth response to exogenous GH in children affected by GHD treated with recombinant human GH (rhGH), and this might open new perspectives in the field of GH pharmacogenetics. On this background, we started a study to verify this hypothesis and in this paper report on the influence of different GHRPs on the response to rhGH in GHD children.

	Subjects and Methods

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We selected 54 prepubertal children (11 females and 43 males) affected by idiopathic GHD, whose parents gave informed consent to their participation in this study. Inclusion criteria were diagnosis of GHD according to conventional criteria (11) and, in particular, short stature (equal to or less than the third percentile for age) or stature short with respect to midparental height (MPH) (12), growth velocity (GV) lower than the 25th percentile for age for at least 1 yr or lower than the 10th percentile for age for at least 6 months, and bone age (BA) delay; peak GH in response to at least two pharmacological stimulation tests (arginine, insulin, or clonidine) lower than 10 ng/ml. We excluded subjects with organic GHD, GHD secondary to radiotherapy, familial (genetic) GHD, or psychosocial GHD and dwarfism; chronic diseases affecting growth; and Turner syndrome. All subjects had isolated GHD, except for one, who also had central hypothyroidism that was adequately substituted with L-T₄ before starting GH treatment. Anthropometric evaluation was performed by trained physicians using standard techniques (12); GV was measured for at least 1 yr before starting rhGH and after the start of treatment at 6-month intervals. We have expressed GV as both in centimeters per year and as SD score (SDS) for sex and age (13).

The main baseline variables are summarized in Table 1. Mean MPH SDS was significantly higher than the height SDS (HtSDS) of the subjects (P < 0.001). Mean BA delay was –1.39 yr (SD, 1.07). The patients received rhGH for at least 1 yr at a weekly dose of 0.2 mg/kg body weight, subdivided into daily sc injections (6 d/wk).

Approval of the study protocol was obtained from the local ethical committee as was written informed consent for DNA sampling and for participation in the study from the subjects’ parents.

Genomic DNA was isolated from peripheral blood of each subject using the 6100 Nucleic Acid PrepStation semiautomatic method (ABI PRISM, Applied Biosystem, Foster City, CA).

All exons were amplified by PCR using the following pairs of intronic primers: exon II: forward, 5'-TGCTGGGCTTTACCTTACC-3'; reverse, 5'-GTTTCAAAACACTGAGGGTG-3' [annealing temperature (AT), 52 C]; exon III: forward, 5'-TACACAGGGTCATATCAGATT-3'; reverse, 5'-CTATTCCAGTTACTACCATCCC-3' (AT, 55 C); exon IV: forward, 5'-ATATGACTCACCTGATTTATG-3'; reverse, 5'-TAGGTACATCCATGGAGAGGAA-3' (AT, 50 C); exon V: forward, 5'-ACTTAAGCTACAACATGATT-3'; reverse, 5'-GCTTCCCCATTTATTATTTAG-3' (AT, 50 C); exon VI: forward, 5'-ATTGTGTCTGTCTGTGTACTAATG-3'; reverse, 5'-ATAGAAAGAAAAGTCAAAGTGTAAG-3' (AT, 57 C); exon VII: forward, 5'-TTGAGTTGTTGACTCTTTGGCC-3'; reverse, 5'-AACTGTTATATTGACAAAAGC-3' (AT, 57 C); exon VIII: forward, 5'-GAAACTGTGCTTCAACTAGTC-3'; reverse, 5'-GGTCTAACACAACTGGTACA-3' (AT, 53 C); exon IX: forward, 5'-GCTATAATTGAGAATATGTAG-3'; reverse, 5'-CATATGACAGGAGTCTTCAGGTG-3' (AT, 50 C); exon Xa: forward, 5'-GAGTTTCTTTTCATAGATCTTC-3'; reverse, 5'-GGCATTGAAATCAGTCTCCAG-3' (AT, 52 C); exon Xb: forward, 5'-GGACGTACCAGCTGTTGTGA-3'; reverse, 5'-CGATGTTTGACAGTGAACTTGG-3' (AT, 53 C); exon Xc: forward, 5'-CACCAAGCTGCCCATATTCAG-3'; reverse, 5'-GGTGATGTAAATGTCCTCTTG-3' (AT, 52 C); and exon Xd: forward, 5'-GGTTGAATCACACATACAGCC-3'; reverse, 5'-TGCCCCAGTCAATTCTTTGCT-3' (AT, 57 C). The coding region of exon 10 was amplified using four overlapping pairs of primers. PCR conditions common to all exons were an initial denaturation of 10 min at 95 C, followed by 38 cycles involving a denaturation step of 94 C, an annealing of 30 sec, and an extension period of 30 sec at 72 C, and a final extension period of 7 min at 72 C. PCR products were visualized on 2% agarose gel stained with ethidium bromide. To determine the genotype at the GHR-exon 3 locus in the patients and thus identify the wild-type alleles (GHR fl) and deleted alleles (GHR d3), we performed a simple multiplex PCR assay using primers G1, G2, and G3 (GenBank accession no. AF155912) as follows: initial step of denaturation of 10 min at 95 C; 35 cycles consisting of 30 sec at 94 C, 30 sec at 59 C, and 1 min and 30 sec at 72 C; and a final extension at 72 C for 7 min. Amplification products were analyzed by electrophoresis on a 2% agarose gel stained with ethidium bromide.

The presence of single or multiple mismatches in the PCR products was revealed by denaturing HPLC (DHPLC). For the formation of homo- and heteroduplices, all PCR products were denatured at 95 C for 3 min and renatured for 10 min at room temperature. Amplicons were then analyzed by the Transgenomic WAVE System (Transgenomic, Omaha, NE) with a linear gradient at a flow rate of 0.9 ml/ml that varied as a function of amplicon size and the following column temperatures: exon II, 59 C; exon III, 54.9–57.9 C; exon IV, 58.2–59.2 C; exon V, 54.7 C; exon VI, 56.2–59 C; exon VII, 55.8 C; exon VIII, 56 C; exon IX, 54.4–55.4 C; exon Xa, 56,7 C; Xb and Xc, 59.1 C; and Xd, 58.3 C.

For exons in which mismatches were found by DHPLC analysis, direct sequencing was performed using the sequence kit Dye Terminator (Applied Biosystems) on an ABI PRISM 210 automatic sequencer (Applera) according to the manufacturer’s protocol.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All children responded to rhGH with an increment in GV, with a gain of 0.64 (SD, 0.38) HtSDS in the first year. The main outcome variables are summarized in Table 1.

Molecular analysis revealed a high frequency of GHRPs, in particular, exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 (Pol 6) in 44 subjects (82%), and polymorphism 1576 A>C at codon 526 of exon 10 (Pol 10) in 35 subjects (65%). These polymorphisms recurred in association in most subjects (Table 2). In five subjects another polymorphism was found in exon 10c, with the substitution of a thymine (T) for a cytosine (C) at position 1419, causing no amino acidic change.

On an univariate model, chronological age at treatment onset directly correlated with baseline IGF-I levels (P < 0.001) and inversely correlated with GV after treatment (P < 0.001); GVSDS before treatment inversely correlated with both DeltaGV (P < 0.01) and DeltaHVSDS (P < 0.01).

By multiple regression analysis, we explored possible influences on the growth response to rhGH by these different variables: age, HtSDS, GV and GVSDS before start of treatment, BA delay, MPHSDS, baseline IGF-I levels, GH peak after the stimulation test, and type of polymorphism or main polymorphism combinations. The only variable that was significantly predictive of growth response to GH was GVSDS before treatment, which showed an inverse correlation with both DeltaGV (P < 0.01) and DeltaGVSDS (P < 0.01).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study, we analyzed the GHR sequence in 54 GHD subjects and investigated possible correlations between the growth response to exogenous rhGH and different GHRPs. The polymorphisms in the GHD subjects recurred and were associated with each other in most cases; in only six subjects did we find the polymorphism Del 3 alone and in only eight subjects did we find the polymorphism Pol 6 alone. We did not observe any correlation between any of the single polymorphisms, alone or in association with others, and the growth response to rhGH in terms of difference in GV during the first year of treatment and GV before the start of treatment. The only variable that inversely correlated with DeltaGV was GVSDS before GH therapy, in keeping with previous reports (1). While carrying on our study, a paper was published by Dos Santos et al. (14) that indicated a possible influence of exon 3 deletion on the growth response to exogenous GH in subjects with ISS or born small for gestational age (SGA). In particular, these researchers reported that the isoform of the GHR gene that lacks exon 3 (Del 3) was associated with a better response to exogenous GH in children with ISS or SGA. These observations were supported by in vitro functional analysis, demonstrating that transduction of the GH signaling through homo- or heterodimers of Del 3 was higher than that through full-length GHR homodimers by about 30%. Therefore, we specifically analyzed a possible influence of polymorphism Del 3 alone or in combination with other polymorphisms and the growth response to rhGH and found no differences. A possible explanation for this finding might be the different category of patients studied by us (GHD) compared with those studied by Dos Santos and co-workers (ISS and SGA). Our results are in accordance with preliminary data reported very recently by other investigators in GHD subjects (15, 16) and are at variance with those reported by others (17). A possible reason for these discrepancies may reside in the different criteria used in selecting the GHD subjects. For example, the subjects studied by us include a whole spectrum of GHD, ranging from severe to partial GHD, as indicated by borderline values of stimulated GH peaks, IGF-I, and HtSDS in some of them. In contrast, polymorphism Del 3 was evenly distributed in our sample (del 3 in 48%; full-length GHR in 52% of our subjects), and this allowed a statistically good comparison between subjects carrying the Del 3 polymorphisms and those with the full-length receptor.

In summary, our study indicates that the most frequent GHRPs do not seem to affect the growth response to exogenous rhGH in subjects with GHD, at variance with what was observed in other categories of children with short stature (10).

	Footnotes

 
First Published Online January 4, 2006

Abbreviations: AT, Annealing temperature; BA, bone age; DHPLC, denaturing high-pressure liquid chromatography; GHD, GH deficiency or GH deficient; GHR, GH receptor; GHRP, GHR polymorphism; GV, growth velocity; ISS, idiopathic short stature; MPH, midparental height; rh, recombinant human; SDS, SD score; SGA, small for gestational age.

Received June 14, 2005.

Accepted December 21, 2005.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pilotta, A. Articles by Buzi, F. Search for Related Content PubMed PubMed Citation Articles by Pilotta, A. Articles by Buzi, F. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology