Stevens Adam, Murray Philip, Wojcik Jerome, Raelson John, Koledova Ekaterina, Chatelain Pierre, Clayton Peter
Faculty of BiologyMedicine and Health, University of Manchester and Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Quartz BioGeneva, Switzerland.
Eur J Endocrinol. 2016 Dec;175(6):633-643. doi: 10.1530/EJE-16-0357. Epub 2016 Sep 20.
Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations.
Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification.
The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes - SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR).
The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use.
在PREDICT长期随访（LTFU）研究（编号Nbib699855）中，先前已在生长激素缺乏症（GHD）和特纳综合征（TS）儿童中鉴定出与重组人生长激素（r-hGH）反应相关的单核苷酸多态性（SNP）。在此，我们描述了PREDICT验证（VAL）研究（编号Nbib1419249），其旨在确认这些基因关联。
从9个国家的29个地点回顾性招募GHD儿童（n = 293）或TS儿童（n = 132）。所有儿童均已完成1年的r-hGH治疗。对先前鉴定为与r-hGH第一年生长反应相关的48个SNP进行基因分型。使用回归分析，以临床/体格学变量作为协变量，评估基因型与生长反应之间的关联。使用随机森林分类进行进一步分析。
VAL研究中的儿童更年幼，生长反应更高。直接基因型分析未重现LTFU研究中的发现。然而，使用带有协变量的探索性回归模型，在VAL和LTFU中，对于四个基因——GHD中的SOS1和INPPL1以及TS中的ESR1和PTPN1，显示出与生长反应的一致关系。随机森林分析表明，在轻度GHD（GH刺激试验中>4至<10μg/L）中，仅临床协变量对生长反应的预测很重要，然而，在重度GHD（≤4μg/L）中，几个SNP有贡献（在IGF2、GRB10、FOS、IGFBP3和GHRHR中）。
PREDICT验证研究在一个独立队列中支持，在控制临床/体格学协变量后，48个遗传标记中的4个与青春期前GHD和TS儿童对r-hGH治疗的生长反应相关。然而，这些SNP在第一年反应预测模型中的贡献不足以用于常规临床应用。
Zotero 插件
