Impact of the Exon 3-Deleted Growth Hormone (GH) Receptor Polymorphism on Baseline Height and the Growth Response to Recombinant Human GH Therapy in GH-Deficient (GHD) and Non-GHD Children with Short Stature: A Systematic Review and Meta-Analysis

Wassenaar, Moniek J. E.; Dekkers, Olaf M.; Pereira, Alberto M.; Wit, Jan M.; Smit, Johannes; Biermasz, Nienke R.; Romijn, J. A.

doi:10.1210/jc.2009-0425

Cited by 98 publications

(88 citation statements)

References 25 publications

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“…47,48 This latter polymorphism was not found to be significantly more frequent in pygmies than in non-pygmies.…”

Section: Resultsmentioning

confidence: 74%

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Becker¹,

Verdu²,

Georges³

et al. 2012

Eur J Hum Genet

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African pygmies are at the lower extreme of human variation in adult stature and many evolutionary hypotheses have been proposed to explain this phenotype. We showed in a recent study that the difference in average stature of about 10 cm observed between contemporary pygmies and neighboring non-pygmies has a genetic component. Nevertheless, the genetic basis of African pygmies' short stature remains unknown. Using a candidate-gene approach, we show that intronic polymorphisms in GH receptor (GHR) and insulin-like growth factor 1 (IGF1) genes present outlying values of the genetic distance between Baka pygmies and their non-pygmy Nzimé neighbors. We further show that GHR and IGF1 genes have experienced divergent natural selection pressures between pygmies and non-pygmies throughout evolution. In addition, these SNPs are associated with stature in a sample composed of 60 pygmies and 30 non-pygmies and this association remains significant when correcting for population structure for the GHR locus. We conclude that the GHR and IGF1 genes may have a role in African pygmies' short stature. The use of phenotypically contrasted populations is a promising strategy to identify new variants associated with complex traits in humans.

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“…47,48 This latter polymorphism was not found to be significantly more frequent in pygmies than in non-pygmies.…”

Section: Resultsmentioning

confidence: 74%

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Becker¹,

Verdu²,

Georges³

et al. 2012

Eur J Hum Genet

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“…The d3-GHR has been suggested to confer a more GH-sensitive receptor, and in GHD short children carriers of the d3-allele have in many studies, although not all, been shown to respond better to GH in terms of growth velocity and final height than noncarriers (7). Studies on adult GHD populations have produced more conflicting data, showing either no association or a better response in carriers of the d3-GHR (8,9,10,11).…”

Section: Introductionmentioning

confidence: 99%

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults

Glad

Barbosa

Nyström

et al. 2014

European Journal of Endocrinology

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Objective: GH-deficient (GHD) adults have reduced serum concentrations of IGF1. GH replacement therapy increases serum IGF1 concentrations, but the interindividual variation in treatment response is large and likely influenced by genetic factors. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in genes within the GH signaling pathway influence the serum IGF1 response to GH replacement. Design and methods: A total of 313 consecutive GHD adults (58.1% men; mean age 49.7 years) were studied before and after 1 week, 6 months, and 1 year of GH treatment. GH dose was individually titrated to normalize serum IGF1 levels. Six SNPs in the GH receptor (GHR) and the GH signaling pathway (JAK2, STAT5B, SOCS2, and PIK3CB) genes were selected for genotyping. The GHR exon 3-deleted/full-length (d3/fl) polymorphism was analyzed using tagSNP rs6873545. Results: After 1 week of GH replacement, homozygotes of the fl-GHR showed a better IGF1 response to GH than carriers of the d3-GHR (PZ0.016). Conversely, homozygotes of the minor allele of PIK3CB SNP rs361072 responded better than carriers of the major allele (PZ0.025). Compared with baseline, both SNPs were associated with the IGF1 response at 6 months (PZ0.041 and PZ0.047 respectively), and SNP rs6873545 was further associated with the IGF1 response at 1 year (PZ0.041). Conclusions: Our results indicate that common genetic variants in the GH signaling pathway may be of functional relevance to the response to GH replacement in GHD adults.

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“…In addition, growth response during the first year of rhGH therapy, expressed both as height SDS gain and as growth velocity, was significantly increased in prepubertal non-GHD and GHD short children bearing the d3-GHR genotype in comparison with the fl-GHR genotype. The meta-analysis found that the presence of d3-GHR allele stimulated growth velocity by an additional effect of approximately 0.5 cm during the first year of rhGH treatment, and such effect was more pronounced at lower rhGH doses and in children of higher age (30).…”

Section: Ghr Polymorphism In Short Childrenmentioning

confidence: 98%

“…Wassenaar et al (30) conducted a systematic review and meta-analysis of 15 studies published between 2004 and 2008, with a range of 28-240 patients included in the series, aiming at assessing the effects of d3-GHR on baseline height and the first year's growth response to rhGH treatment in prepubertal short GHD children (7 studies) and non-GHD children (6 studies in small for gestational age (SGA), 3 studies in idiopathic short stature (ISS) and 2 studies in Turner syndrome). The meta-analysis showed that d3-GHR was associated with increased baseline height in GHD prepubertal children with short stature, but not in non-GHD children.…”

Section: Ghr Polymorphism In Short Childrenmentioning

confidence: 99%

“…The methodological approach used by Wassenaar et al (30) in their systematic review and meta-analysis has been criticized, as the model used to estimate R313 Review C L Boguszewski and others GHR polymorphism in growth and metabolism www.eje-online.org treatment effect comparing d3-GHR carriers vs noncarriers assumed that the underlying inheritance is dominant (31). To overcome this and other potential biases, Renehan et al (31) performed a systematic review including 12 studies and 1527 short children from any cause, using an established Bayesian inheritance modelfree approach to meta-analyze the data and quantify the effects of the d3/fl-GHR and d3-GHR genotypes on rhGH therapy response.…”

Section: Ghr Polymorphism In Short Childrenmentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

Boguszewski

Barbosa

Svensson

et al. 2017

European Journal of Endocrinology

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Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized. The growth hormone receptor (GHR)Growth hormone (GH) exerts its biological effects by binding to the GH receptor (GHR). The GHR protein is positioned at the cell membrane of almost every cell in the human body and contains a 246 amino acids long extracellular (GH-binding) domain, a transmembrane domain and a 350 amino acids long intracellular (cytoplasmic) domain. In total, the GHR protein is composed of 638 residues (1). Binding of GH to the GHR induces a series of subtle conformational events within a receptor homodimer, rather than a simple receptor dimerization, promoting a realignment of the two receptors both by relative rotation and by closer apposition just above the cell membrane (2). The parallel receptor transmembrane domains are converted into a rotated crossover orientation and the lower parts of the transmembrane helices are separated. GHR activation

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Impact of the Exon 3-Deleted Growth Hormone (GH) Receptor Polymorphism on Baseline Height and the Growth Response to Recombinant Human GH Therapy in GH-Deficient (GHD) and Non-GHD Children with Short Stature: A Systematic Review and Meta-Analysis

Cited by 98 publications

References 25 publications

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults

MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

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