Diagnosis of Childhood Growth Hormone Deficiency and Prediction of Therapeutic Response Using Gene Expression Data

利用基因表达数据诊断儿童生长激素缺乏症并预测治疗反应

• 批准号: MR/T024119/1
• 负责人: Philip Murray
• 金额: $ 40.06万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT024119%2F1
• 关键词: Diagnosis; Childhood; Growth; Hormone; Deficiency

Growth Hormone Deficiency is a condition in which children grow very poorly without treatment with injections of growth hormone. It is very important to make this diagnosis as children with growth hormone deficiency will grow to a normal height if treated. Currently to make a diagnosis of growth hormone deficiency doctors need to undertake a combination of blood tests and brain scans. It is very difficult to measure growth hormone during the day as children produce this hormone only overnight. Since blood tests overnight are not easy doctors use special type of test called a stimulation test to diagnose growth hormone deficiency using blood taken during the day. The stimulation tests involve children having a drip placed in an arm, administration of medication via the drip (this medication causes the body to produce growth hormone) and many blood samples over the next 3 hours. The medication often have side effects such as nausea and vomiting. These tests require the child to be admitted to a hospital ward for the morning and a dedicated nurse to do the test thus they are relatively expensive for the NHS. We have started to develop a new method for testing if a child has low growth hormone levels using the level of gene activity in the blood. This test uses a single blood sample, does not require the use of mediation (thus avoiding any unpleasant side effects) and would not require the child to be admitted to hospital. The test works by measuring the activity levels of all the genes in the blood and the using a mathematical technique called Random Forest Analysis to tell whether children have low growth hormone levels or not. Our initial studies have indicated that this test works extremely well but before it is rolled out across the NHS we need to test it on larger number of children to be completely sure that it works. We will therefore recruit another 60 children with low growth hormone levels and 60 children with normal growth hormone levels from the Royal Manchester Children's Hospital. Each child will have a blood sample taken to measure their gene activity levels and we will then compare how accurate our test is compared to the results of the current growth hormone stimulation tests. Once children are diagnosed with growth hormone deficiency they are treated with injections of growth hormone once each day. Although generally this treatment works well sometimes children don't respond to the treatment. At the moment the only way of telling who will respond is to give them injections for 6-12 months and measure how well they grow. We have been able to show that the gene expression levels measured on the same test we use to diagnose Growth Hormone Deficiency can also tell us who will not respond to treatment. It would be great to identify those children who won't respond to treatment so we could either give them a larger dose of growth hormone or in some cases we may choose not to treat them (thus the child avoids up to 1 year of ineffective daily injections). Once again we need to confirm our initial findings in a second group of children. For those children with growth hormone deficiency recruited to the study we will look 1 year after treatment to see who has responded well and who has responded badly. We will then use the gene expression levels and the Random Forest Analysis technique to validate out technique for predicting who does not respond well to treatment. The result of this study is that with one blood sample we will be able to 1. Tell if a child has low growth hormone levels - saving the child side effects from medication, the need for multiple blood tests and saving the NHS significant bed and nursing time2. Tell whether a child will grow well when treated with growth hormone. This may save the child a year of unnecessary injections or allow us to use a higher dose to ensure they do benefit from the injections.

生长激素缺乏症是一种儿童在没有注射生长激素治疗的情况下生长非常差的情况。这是非常重要的，使这个诊断为生长激素缺乏症的儿童将生长到正常的高度，如果治疗。目前，要诊断生长激素缺乏症，医生需要结合血液检查和脑部扫描。白天测量生长激素非常困难，因为儿童只在一夜之间产生这种激素。由于夜间验血并不容易，医生使用特殊类型的测试称为刺激测试，以诊断生长激素缺乏症使用血液在白天采取。刺激测试涉及在手臂上放置点滴的儿童，通过点滴给药（这种药物会导致身体产生生长激素）和在接下来的3个小时内的许多血液样本。这种药物通常有副作用，如恶心和呕吐。这些测试需要孩子被送往医院病房的早晨和一个专门的护士做测试，因此他们是相对昂贵的国民保健服务。我们已经开始开发一种新的方法来测试如果一个孩子有低生长激素水平使用血液中的基因活性水平。这种测试使用单一的血液样本，不需要使用调解（从而避免任何不愉快的副作用），也不需要孩子住院。该测试通过测量血液中所有基因的活性水平，并使用称为随机森林分析的数学技术来判断儿童是否具有低生长激素水平。我们的初步研究表明，这种测试效果非常好，但在它在整个NHS推出之前，我们需要在更多的儿童身上进行测试，以完全确保它的效果。因此，我们将从皇家曼彻斯特儿童医院招募另外60名生长激素水平低的儿童和60名生长激素水平正常的儿童。每个孩子都将有一个血液样本，以测量他们的基因活性水平，然后我们将比较我们的测试是如何准确相比，目前的生长激素刺激测试的结果。一旦儿童被诊断患有生长激素缺乏症，他们每天注射一次生长激素。虽然一般来说这种治疗效果很好，但有时儿童对治疗没有反应。目前，判断谁会有反应的唯一方法是给他们注射6-12个月，并测量他们的生长情况。我们已经能够证明，在我们用来诊断生长激素缺乏症的同一测试中测量的基因表达水平也可以告诉我们谁对治疗没有反应。最好能识别出那些对治疗没有反应的儿童，这样我们就可以给他们更大剂量的生长激素，或者在某些情况下我们可以选择不治疗他们（这样孩子就可以避免长达1年的无效每日注射）。我们需要再次证实我们在第二组儿童中的初步发现。对于那些生长激素缺乏症的儿童，我们将在治疗后1年观察谁反应良好，谁反应不良。然后，我们将使用基因表达水平和随机森林分析技术来验证预测谁对治疗反应不佳的技术。这项研究的结果是，一个血液样本，我们将能够1。告诉如果一个孩子有低生长激素水平-节省孩子的药物副作用，需要多次血液检查和节省NHS显着的床和护理时间2。告诉一个孩子是否会生长良好时，用生长激素治疗。这可能会为孩子节省一年不必要的注射，或者允许我们使用更高的剂量，以确保他们确实从注射中受益。

项目成果

Gene expression signatures predict response to therapy with growth hormone.

• DOI: 10.1038/s41397-021-00237-5
• 发表时间: 2021-10
• 期刊: The pharmacogenomics journal
• 作者: Stevens A;Murray P;De Leonibus C;Garner T;Koledova E;Ambler G;Kapelari K;Binder G;Maghnie M;Zucchini S;Bashnina E;Skorodok J;Yeste D;Belgorosky A;Siguero JL;Coutant R;Vangsøy-Hansen E;Hagenäs L;Dahlgren J;Deal C;Chatelain P;Clayton P
• 通讯作者: Clayton P

Role of ZBTB38 Genotype and Expression in Growth and Response to Recombinant Human Growth Hormone Treatment.

• DOI: 10.1210/jendso/bvac006
• 发表时间: 2022-03-01
• 期刊: Journal of the Endocrine Society
• 影响因子: 4.1
• 作者: Parsons S;Stevens A;Whatmore A;Clayton PE;Murray PG
• 通讯作者: Murray PG

Pharmacogenomics applied to recombinant human growth hormone responses in children with short stature.

• DOI: 10.1007/s11154-021-09637-1
• 发表时间: 2021-03
• 期刊: Reviews in endocrine & metabolic disorders
• 影响因子: 8.2
• 作者: Stevens A;Perchard R;Garner T;Clayton P;Murray P
• 通讯作者: Murray P

Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology.

先天性甲状腺功能减退症：2020 - 2021年共识指南更新 - 欧洲欧洲参考网络倡议由欧洲儿科内分泌学会和欧洲内分泌学会认可。

• DOI: 10.1089/thy.2020.0333
• 发表时间: 2021-03
• 期刊: Thyroid : official journal of the American Thyroid Association
• 作者: van Trotsenburg P;Stoupa A;Léger J;Rohrer T;Peters C;Fugazzola L;Cassio A;Heinrichs C;Beauloye V;Pohlenz J;Rodien P;Coutant R;Szinnai G;Murray P;Bartés B;Luton D;Salerno M;de Sanctis L;Vigone M;Krude H;Persani L;Polak M
• 通讯作者: Polak M

Diagnosis of childhood and adolescent growth hormone deficiency using transcriptomic data.

• DOI: 10.3389/fendo.2023.1026187
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2