The in vitro functional analysis of single-nucleotide polymorphisms associated with growth hormone (GH) response in children with GH deficiency
The in vitro functional analysis of single-nucleotide polymorphisms associated with growth hormone (GH) response in children with GH deficiency
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DOI：
10.1038/s41397-018-0026-4
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发表时间：
2019-04-01
影响因子：
2.8
通讯作者：
Stevens, Adam
中科院分区：
文献类型：
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作者：
De Leonibus, Chiara;Murray, Philip;Stevens, Adam
在治疗的第一年对重组人生长激素（r-hGH）的反应与GH缺乏症（GHD）儿童的单核苷酸多态性（SNP）相关。使用计算机模拟技术的组合筛选相关SNP的调节功能。选择调控序列中的4个SNPs进行体外转录活性（TA）分析。这四个基因中的等位基因存在加性效应，与良好的生长反应相关。对于IGFBP 3中的rs3110697、CYP 19 A1中的rs 1045992和SOS 1中的rs 2888586，与更好的生长反应相关的变体显示r-hGH处理的TA更高。对于GRB 10中的rs 1024531（IGF-I信号传导和生长的负调节因子），与更好的生长反应相关的变体在r-hGH刺激下具有显著较低的TA。这些结果表明，特定的SNP变体对TA有影响，这为它们对r-hGH治疗的生长反应的临床影响提供了依据。
Response to recombinant human growth hormone (r-hGH) in the first year of therapy has been associated with single-nucleotide polymorphisms (SNPs) in children with GH deficiency (GHD). Associated SNPs were screened for regulatory function using a combination of in silico techniques. Four SNPs in regulatory sequences were selected for the analysis of in vitro transcriptional activity (TA). There was an additive effect of the alleles in the four genes associated with good growth response. For rs3110697 within IGFBP3, rs1045992 in CYP19A1 and rs2888586 in SOS1, the variant associated with better growth response showed higher TA with r-hGH treatment. For rs1024531 in GRB10, a negative regulator of IGF-I signalling and growth, the variant associated with better growth response had a significantly lower TA on r-hGH stimulation. These results indicate that specific SNP variants have effects on TA that provide a rationale for their clinical impact on growth response to r-hGH therapy.