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  • 1
    Online Resource
    Online Resource
    Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms
    Future Medicine Ltd ; 2009
    In:  Pharmacogenomics Vol. 10, No. 2 ( 2009-02), p. 293-302
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 10, No. 2 ( 2009-02), p. 293-302
    Abstract: Aims: Several SNPs and a microsatellite cytosine–adenine repeat promoter polymorphism of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth hormone (GH) treatment, resulting in different individually required GH-doses in GH-deficient patients. The aim of this study was to test if the IGF-1 gene polymorphisms are associated with the GH-dose of GH-deficient adults. Materials & methods: A total of nine tagging SNPs, five additionally selected SNPs and a cytosine–adenine repeat polymorphism were determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years ± 13.1 standard deviation; majority Caucasian) with GH-deficiency (GHD) of different origin, derived from the prospective Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH-dose after 1 year of treatment, IGF-1 concentrations, IGF-1-standard deviation score (SDS), the IGF-1:GH ratio and anthropometric data were analyzed by genotype. Results: Except for rs1019731, which showed a significant difference of IGF-1-SDS by genotypes (p = 0.02), all polymorphisms showed no associations with the GH-doses, IGF-1 concentrations, IGF-1-SDS and IGF-1:GH ratio after adjusting for the confounding variables gender, age and BMI. Conclusion: IGF-1 gene polymorphisms were not associated with the responsiveness to exogenous GH in GHD. Therefore, genetic variations of the IGF-1 gene seem not to be major influencing factors of the GH–IGF-axis causing variable response to exogenous GH-treatment.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/14622416.10.2.293
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2009
    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    Additive effect of GHRd3 and COLIA1 polymorphisms on the GH-substitution dose in GH-deficient adults
    Future Medicine Ltd ; 2011
    In:  Pharmacogenomics Vol. 12, No. 12 ( 2011-12), p. 1653-1661
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 12, No. 12 ( 2011-12), p. 1653-1661
    Abstract: The exon 3-deleted/full-length growth hormone receptor (GHRd3) polymorphism and the collagen type Iα 1-specific protein 1 (COLIA1) polymorphism have each recently been linked to the responsiveness to recombinant growth hormone (GH) treatment in GH-deficient adults. In this context, one or two GHRd3 alleles and the homozygous COLIA1 TT genotype were each associated with a significantly lower GH dose. Aim: The aim of this pilot study was to test if these polymorphisms together have an additive effect on the individually required GH dose in adults with GH deficiency. Patients & methods: The GHRd3 and COLIA1 polymorphisms were determined in 130 German adult patients (65 men, 65 women; mean age: 45.9 years ± 12.9 SD; majority Caucasian) with GH deficiency of different origin, derived from the prospective KIMS Pharmacogenetics Study. Patients received GH treatment for at least 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH dose after 1 year of treatment, IGF-1 concentrations, IGF-1 standard deviation score and anthropometric data were analyzed according to genotype group. Results: Concerning etiology, gender, age, anthropometric data, IGF-1 concentrations and IGF-1 standard deviation score, study subjects demonstrated no significant differences by genotype. After 1 year of GH treatment, the GH dose in the GH-deficient patients carrying one or two alleles of the growth hormone receptor (GHR) exon 3 deletion and the TT genotype of the COLIA1 polymorphism was on average half the dose required in patients with the full-length GHR (fl/fl) and the homozygous COLIA1 GG genotype (p = 0.045). Conclusion: Carriers of one or two alleles of the GHR exon 3 deletion and COLIA1 TT genotype require significantly lower GH doses as compared with both homozygous fl GHR and COLIA1 GG genotype carriers. There seems to be an additive effect of both polymorphisms on the individually required GH dose in GH-deficient adults which may serve to explain part of the variability of the required amounts of exogenous GH in these patients. Original submitted 20 April 2011; Revision submitted 14 July 2011
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs.11.113
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2011
    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    Association of COLIA1 Sp1 polymorphism with the effect of subcutaneously injected recombinant hGH in GH-deficient adults
    Future Medicine Ltd ; 2008
    In:  Pharmacogenomics Vol. 9, No. 8 ( 2008-08), p. 1017-1026
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 9, No. 8 ( 2008-08), p. 1017-1026
    Abstract: Objective: Collagen type I is a common structural protein in bone and skin. Similar to its association with the mechanical properties of the skeleton and, thus, bone-fracture risk, the collagen type I α (COLIA)-1 specific protein (Sp)-1 polymorphism may be related to variations in the collagen type I-containing subcutaneous tissue and its biological properties. In this study, we analyzed a possible influence of the COLIA1 Sp1 polymorphism on the effect of subcutaneously injected recombinant human growth hormone (hGH) in GH-deficient adults. Materials & methods: We determined the COLIA1 Sp1 polymorphism in 122 adults with GH deficiency of different origin, who were derived from the prospective Pfizer International Growth Database (KIMS) Pharmacogenetics Study. Inclusion criteria were subcutaneous applied treatment with hGH for over 12 months, finished dose titration of hGH by following serum IGF-1 concentrations until desired levels were achieved, and centralized, standardized IGF-1 measurements. The genotypes (GG/GT/TT) were statistically related to clinical data from the KIMS database. Results: The dose of injected hGH was significantly related to the COLIA1 Sp1 genotypes (p = 0.049), whereby the GG homozygotes were treated with a significantly higher dose of hGH than TT homozygotes (p = 0.03). Accordingly, the IGF-1:GH ratios were significantly lower in GG compared with TT homozygotes (p = 0.04). Both groups showed no significant differences in their IGF-1 serum concentrations (p = 0.98) and IGF-1 SDS (p = 0.79). Conclusion: The COLIA1 Sp1 polymorphism is related to the dose of individually required, subcutaneous injected hGH in GH-deficient adults, probably because of an alteration of the subcutaneous collagen type I structure, content and/or biological/biomechanical properties. GG homozygotism, which is related to a more stable bone structure and decreased fracture risk, may impact skin resistance to subcutaneous injected protein-based drugs, as shown for hGH in this study.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/14622416.9.8.1017
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2008
    SSG: 15,3
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  • 4
    Online Resource
    Online Resource
    Association of the exon 3 deleted/full-length GHR polymorphism with recombinant growth hormone dose in growth hormone-deficient adults
    Future Medicine Ltd ; 2009
    In:  Pharmacogenomics Vol. 10, No. 10 ( 2009-10), p. 1599-1608
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 10, No. 10 ( 2009-10), p. 1599-1608
    Abstract: Aims: Contradictory reports exist regarding the influence of the exon 3 deleted (d3)/full-length (fl) growth hormone receptor (GHR) polymorphism on responsiveness to recombinant human growth-hormone therapy in idiopathic short stature, small for gestational age and GH-deficient children, Turner syndrome patients and GH-deficient adults. In some of these studies, the d3 allele was associated with increased responsiveness to GH. The aim of this study was to test this association in a group of GH-deficient adult patients receiving recombinant GH treatment. Materials & methods: Patients were derived from the prospective German Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. The GHRd3/fl polymorphism was determined in 133 German adult patients (66 men and 67 women; mean age: 45.4 years ± 13.1 standard deviation; majority Caucasian) with a GH-deficiency of different origin. Patients received GH treatment for 12 months with a finished dose-titration of GH and standardized insulin-like growth factor (IGF)-1 measurements in one central laboratory. GH dose after 1 year of treatment, IGF-1 serum concentrations, IGF-1 standard deviation score (SDS) values and anthropometric data were analyzed by GHRd3/fl genotypes. Results: After 1 year of GH treatment, the individually required GH dose was significantly lower in GH-deficient patients carrying one or two d3 alleles, compared with patients with the full-length receptor (p = 0.04). Genotype groups (d3-allele carriers vs noncarriers) showed no significant differences in IGF-1 serum concentrations (p = 0.51), IGF-1 SDS (p = 0.36) nor in gender (p = 0.53), age (p = 0.28), weight (p = 0.13), height (p = 0.53) or BMI (p = 0.15). Conclusion: The d3-allele carriers required approximately 25% less exogenous GH compared with the homozygous fl-allele carriers, which may express an increased responsiveness to exogenous GH. Variability of the individually required GH dose in adult GH-deficient patients may therefore be partly due to the GHRd3/fl polymorphism. Further studies are required to confirm these results.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs.09.91
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2009
    SSG: 15,3
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