Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome

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Abstract

Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) ( n=166) or Turner syndrome (TS) ( n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I ( P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS ( r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose.

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Modularity and community structure in networks

M. Newman (2006)

Many networks of interest in the sciences, including a variety of social and biological networks, are found to divide naturally into communities or modules. The problem of detecting and characterizing this community structure has attracted considerable recent attention. One of the most sensitive detection methods is optimization of the quality function known as "modularity" over the possible divisions of a network, but direct application of this method using, for instance, simulated annealing is computationally costly. Here we show that the modularity can be reformulated in terms of the eigenvectors of a new characteristic matrix for the network, which we call the modularity matrix, and that this reformulation leads to a spectral algorithm for community detection that returns results of better quality than competing methods in noticeably shorter running times. We demonstrate the algorithm with applications to several network data sets.

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Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3).

Martin Elmlinger, Werner Kühnel, Matthias M. Weber … (2004)

Assays for insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) have become essential tools in the diagnostic work-up of disorders of the somatotropic axis in children and adults. The aim of this study was to evaluate the automated IMMULITE IGF-I and IGFBP-3 assays and to establish reference limits--central 95% intervals, median, 0.1 and other centiles as clinically relevant--as a function of age from 797 females and 787 males, from the first week of life through the ninth decade. Pubertal children were classified by sex and by sexual maturation (Tanner stage). IGF-I and IGFBP-3 levels were also assayed in 20 pediatric patients each with growth hormone deficiency (GHD) and Turner syndrome (UTS), before and during 12 months of recombinant growth hormone (rhGH) therapy, as well as in 11 adult patients with GHD and seven with acromegaly before therapy. Both the IGF-I and IGFBP-3 assays were accurate, specific and sufficiently sensitive to measure IGF-I and IGFBP-3 in serum with good linearity and recovery. In the IGF-I assay, potential interference from IGFBPs was eliminated by blocking with excess IGF-II. Circulating IGF-I and IGFBP-3 concentrations, and their ratio IGF-I/IGFBP-3, were age-dependent, showing low levels immediately after birth, a typical pubertal peak for girls and boys, and a pronounced decline after puberty, reaching a plateau in early adulthood. In adults IGF-I and IGFBP-3 levels decreased smoothly but steadily with age. Children with GHD and UTS had low circulating IGF-I and IGFBP-3 levels which increased to normal reference limits under therapy with rhGH. Adult GHD patients showed IGF-I levels below the age-related median; untreated acromegalic patients mostly had IGF-I and IGFBP-3 levels above the age-related 97.5th centile. In conclusion, the automated IMMULITE IGF-I and IGFBP-3 assays are reliable tools in the diagnosis of pathologies of the GH/IGF axis and in the follow-up of their therapies.

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Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables.

Anders Lindberg, , Michael B. Ranke (2010)

Information about the expected growth response of children to GH therapy is currently inadequate. The aim of the study was to compare observed and expected growth in response to GH in prepubertal children and to propose how these parameters can be used to optimize GH therapy. Indices considered were observed growth, observed growth relative to reference data [height sd score (Ht SDS), change in (Delta) Ht SDS, height velocity (HV)], and observed growth relative to growth predicted from prediction models [Studentized residual (SR)]. Design/Setting/Patients/Intervention: Growth data from KIGS-Pfizer International Growth Database-on prepubertal children aged 1-13 yr with severe GH deficiency (GHD; maxGH <5 microg/liter; n = 2129), with less-severe GHD (maxGH of 5-10 microg/liter; n = 3075), and with Turner syndrome (n = 2350), and short children born small for gestational age (n = 993) were analyzed before and during 2 yr of GH treatment. For each patient group, growth responses during the first 2 yr of GH treatment were established. The relationships of HV and DeltaHt SDS with SR were determined. Reference data were generated for assessing adequate individual responses. Responses to GH in terms of HV and DeltaHt SDS were greatest in children with severe GHD. HV and DeltaHt SDS were highly correlated with SR during only the first year of GH treatment (R approximately 0.7; P < 0.001). Decisions on GH therapy regimens should be made using both traditional (HV or DeltaHt SDS) and prediction model-derived (SR) indices of growth response.

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Author and article information

Journal

Journal ID (nlm-ta): Pharmacogenomics J

Journal ID (iso-abbrev): Pharmacogenomics J

Title: The Pharmacogenomics Journal

Publisher: Nature Publishing Group

ISSN (Print): 1470-269X

ISSN (Electronic): 1473-1150

Publication date (Print): February 2014

Publication date (Electronic): 09 April 2013

Volume: 14

Issue: 1

Pages: 54-62

Affiliations

[1 ]Manchester Academic Health Sciences Centre, Royal Manchester Children's Hospital , Manchester, UK

[2 ]Clinica Pediatrica, Università degli Studi di Verona , Verona, Italy

[3 ]Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea

[4 ]Paediatric Endocrine Unit, Hospital General Universitario Gregorio Marañón and Universidad Complutense , Madrid, Spain

[5 ]St Petersburg State Pediatric Medical Academy, Department of Endocrinology , St Petersburg, Russia

[6 ]Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead , Sydney, New South Wales, Australia

[7 ]Merck Serono S.A.—Geneva , Geneva, Switzerland

[8 ]Merck KGaA , Darmstadt, Germany

[9 ]Genizon Biosciences , St Laurent, Quebec, Canada

[10 ]Department Pediatrie, Service d'Endocrinologie & Diabétologie Pédiatriques, Hôpital Mère-Enfant—Université Claude Bernard , Lyon, France

Author notes

[* ]Department Pediatrie, Service d'Endocrinologie & Diabétologie Pédiatriques, Hôpital Mère Enfant de Lyon—Université Claude Bernard , 59 Boulevard Pinel, Lyon, 69677 Bron cedex, France. E-mail: pierre.chatelain@ 123456chu-lyon.fr

[11]

Merck Serono S.A.—Geneva is a branch of Merck Serono S.A., Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.

[12]

Current address: PGx-Services, Montreal, Canada.

[13]

For the complete list of members of this group, see appendix.

Article

Publisher Item ID: tpj201314

DOI: 10.1038/tpj.2013.14

PMC ID: 3959225

PubMed ID: 23567489

SO-VID: 7e095767-0e60-45c5-ab4b-6398aa5310fb

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

History

Date received : 19 July 2012

Date revision received : 22 January 2013

Date accepted : 04 February 2013

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Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome

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Most cited references 32

Modularity and community structure in networks

Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3).

Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables.

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