Growth Hormone Receptor Polymorphism and Growth Hormone Therapy Response in Children: A Bayesian Meta-Analysis

Introduction: GH activity may be involved in male reproductive function. A common genetic polymorphism in the gene encoding the GH receptor (GHR) results in deletion of the entire exon 3 sequence (GHRd3 isoform). The short GHRd3/d3 isoform seems more sensitive compared with full-length receptors (GHRfl/fl). Aim: To investigate the associations between GH activity, evaluated by exon 3 GHR polymorphism, and serum IGF1 vs reproductive hormones, semen quality, and pre-and postnatal growth in healthy young males (nZ838, mean age: 19.4 years). Results: Compared with GHRfl/fl homozygous individuals (nZ467) GHRd3/d3 homozygous individuals (nZ69) tended to have larger semen volume (3.2 (2.4-4.3) vs 3.6 (2.6-4.7) ml, PZ0.053) and higher serum inhibin-B levels (208 pg/ml (158-257) vs 227 pg/ml (185-264), PZ0.050). Semen quality, levels of gonadotropins, testosterone, estradiol, sex hormone-binding globulin, and IGF1 were not associated with GHRd3 genotype. A twofold increase in serum IGF1 was associated with a 13% (4-23) increase in calculated free testosterone (PZ0.004). By contrast IGF1 was inversely associated with serum inhibin-B (PZ0.027), but showed no associations to semen quality. GHR genotype and serum IGF1 were not associated with size at birth or final height. Conclusions: GHRd3 polymorphism seemed only to have a weak influence on male reproductive function of borderline significance. The sensitive GHRd3/d3 genotype may slightly increase testicular function, as evaluated by semen volume and levels of inhibin-B, but does not seem to influence Leydig cell steroidogenesis. GHR genotype did not influence pre-and postnatal growth.

Section: Pre-and Postnatal Growthmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men

Andreassen

Jensen

Jørgensen

et al. 2014

“…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%

“…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. Their primary outcome was the 1-year change in height SDS for the two genotypes.…”

Section: Ghr Polymorphism In Short Childrenmentioning

confidence: 99%

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

Boguszewski

Barbosa

Svensson

et al. 2017

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

“…Clinical data from GH treatment studies in adult populations have demonstrated conflicting results with reports of both increased (13) and decreased (14) responses to GH in carriers of the d3-GHR. In children, however, the d3-GHR has been confirmed to confer a larger growth response to GH in meta-analyses (15,16).…”

Section: Introductionmentioning

confidence: 99%

The GH receptor exon 3 deleted/full-length polymorphism is associated with central adiposity in the general population

Glad

Carlsson

Melander

et al. 2015

Objective: To test the hypothesis that the GH receptor (GHR) exon 3 deleted (d3)/full-length (fl) polymorphism influences anthropometry and body composition in the general population. Design and setting: The Swedish Obese Subjects (SOS) reference study is a cross-sectional population-based study, randomly selected from a population registry. A subgroup of the population-based Malmö Diet and Cancer study (MDC-CC) was used as a replication cohort. Methods: The SOS reference study comprises 1135 subjects (46.2% men), with an average age of 49.5 years. The MDC-CC includes 5451 successfully genotyped subjects (41.5% men), with an average age of 57.5 years. GHR d3/fl genotypes were determined using TagSNP rs6873545. Linear regression analyses were used to test for genotype-phenotype associations. Results: In the SOS reference study, subjects homozygous for the d3-GHR weighed w4 kg more (PZ0.011), and had larger waist-to-hip ratio (WHR, PZ0.036), larger waist circumference (PZ0.016), and more fat-free mass estimated from total body potassium (PZ0.026) than grouped fl/d3 and fl/fl subjects (d3-recessive genetic model). The association with WHR was replicated in the MDC-CC (PZ0.002), but not those with other anthropometric traits. Conclusions: In this population-based study, the GHR d3/fl polymorphism was found to be of functional relevance and associated with central adiposity, such that subjects homozygous for the d3-GHR showed an increased abdominal obesity.