Growth hormone (GH) pharmacogenetics: Influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency
Growth hormone (GH) pharmacogenetics: Influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency
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DOI：
10.1210/jc.2005-2005
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发表时间：
2006-03-01
影响因子：
5.8
通讯作者：
Arnhold, IJP
中科院分区：
文献类型：
--
作者：
Jorge, AAL;Marchisotti, FG;Arnhold, IJP
内容：GHR基因的多态性，外显子3的存在或缺失，已被证明会影响无GH缺乏症（GHD）儿童对人重组GH（hGH）治疗的1年和2年生长反应。目的：本研究的目的是评估GHR外显子3基因型对GHD儿童对hGH治疗的短期和长期反应的影响。研究在大学医院进行。设计和患者：对75名GHD儿童的数据进行基因型和回顾性分析。干预：干预包括平均剂量为33 μ g/kg.d的hGH治疗和多重PCR检测的GHR外显子3基因型。主要结果测量：主要结果测量为GHR基因型：全长（fl）和外显子3缺失（d3）等位基因，在第一年期间保持青春期前的58名儿童的生长速度，以及治疗7.5 +/- 3.0年后的44名GHD患者的成人身高。不同GHR-外显子3基因型患者在治疗开始时的临床和实验室数据以及hGH剂量无法区分（fl/fl对fl/d3或d3/d3）。携带至少一个GHRd 3等位基因的患者在hGH替代治疗的第一年生长速度显著更好（12.3 +/- 2.6 vs. 10.6 +/- 2.3 cm/yr; P < 0.05），并获得更高的成年身高（最终身高SD评分，-0.8 +/-1.1对-1.7 +/-1.2; P < 0.05）。结论：GHR外显子3 fl纯合的GHD患者对短期和长期hGH治疗的反应较低。大约一半的人群是GHRfl纯合子，未来的研究调整hGH治疗基因型可能会改善结果。
Context: A polymorphism in GHR gene, the presence or absence of exon 3, has been shown to influence the 1- and 2-yr growth responses to human recombinant GH (hGH) therapy in children without GH deficiency (GHD).Objective: The objective of this study was to assess the influence of GHR-exon-3 genotype on the short and long-term response to hGH therapy in children with GHD.Setting: The study was conducted in the university hospital.Design and Patients: Genotype and retrospective analysis was performed on data of 75 children with GHD.Intervention: Intervention consisted of hGH treatment at a mean dose of 33 mu g/kg.d and GHR-exon-3 genotype by multiplex PCR.Main Outcome Measures: The main outcome measures were GHR genotype: full-length (fl) and exon 3-deleted (d3) alleles, growth velocity in 58 children who remained prepubertal during the first year, and adult height in 44 patients with GHD after 7.5 +/- 3.0 yr of treatment.Results: Clinical and laboratory data at the start of treatment and hGH doses were indistinguishable among patients with different GHR-exon-3 genotypes (fl/fl vs. fl/d3 or d3/d3). Patients carrying at least one GHRd3 allele had a significantly better growth velocity in the first year of hGH replacement (12.3 +/- 2.6 vs. 10.6 +/- 2.3 cm/yr; P < 0.05) and achieved a taller adult height (final height SD score, -0.8 +/- 1.1 vs. -1.7 +/- 1.2; P < 0.05) when compared with patients homozygous for GHRfl alleles.Conclusions: Patients with GHD who are homozygous for GHR exon 3 fl were less responsive to short- and long-term hGH therapy. Approximately half of the population is homozygous for GHRfl, and future studies adjusting hGH therapy to genotype may improve outcome.