Influence of the Exon 3-Deleted/Full-Length Growth Hormone (GH) Receptor Polymorphism on the Response to GH Replacement Therapy in Adults with Severe GH Deficiency

Svensson

et al. 2017

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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

Section: Ghr Polymorphism In Adults With Growth Hormone Deficiency (Ghd)contrasting

confidence: 99%

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

Boguszewski

Svensson

et al. 2017

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“…Another study showed that d3-GHR carriers require w25% less GH during replacement therapy than fl-GHR carriers (10). Other studies have, however, not shown associations between d3/fl genotype and response to GH in adults (8,9). …”

Section: Discussionmentioning

confidence: 99%

“…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). Previous studies have, however, focused on the long-term (O6 months) response to GH replacement therapy, rather than the early response.…”

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

Nyström

et al. 2014

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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.

“…Previous studies in GHD adults have found an association between the response to GH and clinical and biochemical parameters, such as body mass index (BMI), age, gender, serum GH-binding protein (GHBP) levels, GH dose, and the route of estrogen replacement in women (2,(11)(12)(13)(14)(15)(16). More recently, a genetic predictor, the GH receptor (GHR) polymorphism, has been studied in both children and adults with GHD, showing only a weak influence on the clinical response to GH therapy (17)(18)(19) or no influence at all (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Models to predict changes in serum IGF1 and body composition in response to GH replacement therapy in GH-deficient adults

Korányi²,

Filipsson³

et al. 2010

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Objective: Clinical response to GH therapy in GH-deficient (GHD) adults varies widely. Good predictors of treatment response are lacking. The aim of the study was to develop mathematical models to predict changes in serum IGF1 and body composition (BC) in response to GH therapy in GHD adults. Design and methods: One hundred and sixty-seven GHD patients (103 men, median age 50 years) were studied before and after 12 months of GH treatment. GH dose was tailored according to serum IGF1 concentrations. Good responders (GR) and poor responders (PR) to GH therapy were defined as patients with a response O60th and !40th percentile respectively, for changes in serum IGF1 levels (adjusted for GH cumulative dose) and in BC (lean body mass (LBM) and body fat determined using dual-energy X-ray absorptiometry). A logistic regression model was used to predict the probability of being a GR or PR. Results: In the IGF1 prediction model, men (odds ratio (OR) 5.62: 95% confidence interval 2.59-12.18) and patients with higher insulin levels (OR 1.06: 1.00-1.12) were more likely to be GR. The accuracy of the prediction model was 70%. In the BC model, men ) and GHD patients with lower LBM (OR 0.82: 0.73-0.92) and greater height (OR 1.23: 1.08-1.40) at baseline were more likely to be GR. The accuracy of the prediction model was 80%. Conclusion: Accurate mathematical models to predict GH responsiveness in GHD adults were developed using gender, body height, baseline LBM, and serum insulin levels as the major clinical predictors.