Abnormal DNA methylation within genes of the steroidogenesis pathway two years after paediatric critical illness and association with stunted growth in height further in time.

IF 5.7 2区 医学 Q1 Medicine
Ilse Vanhorebeek, Grégoire Coppens, Fabian Güiza, Inge Derese, Pieter J Wouters, Koen F Joosten, Sascha C Verbruggen, Greet Van den Berghe
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引用次数: 0

Abstract

Background: Former critically ill children show an epigenetic age deceleration 2 years after paediatric intensive care unit (PICU) admission as compared with normally developing healthy children, with stunted growth in height 2 years further in time as physical correlate. This was particularly pronounced in children who were 6 years or older at the time of critical illness. As this age roughly corresponds to the onset of adrenarche and further pubertal development, a relation with altered activation of endocrine pathways is plausible. We hypothesised that children who have been admitted to the PICU, sex- and age-dependently show long-term abnormal DNA methylation within genes involved in steroid hormone synthesis or steroid sulphation/desulphation, possibly aggravated by in-PICU glucocorticoid treatment, which may contribute to stunted growth in height further in time after critical illness.

Results: In this preplanned secondary analysis of the multicentre PEPaNIC-RCT and its follow-up, we compared the methylation status of genes involved in the biosynthesis of steroid hormones (aldosterone, cortisol and sex hormones) and steroid sulphation/desulphation in buccal mucosa DNA (Infinium HumanMethylation EPIC BeadChip) from former PICU patients at 2-year follow-up (n = 818) and healthy children with comparable sex and age (n = 392). Adjusting for technical variation and baseline risk factors and corrected for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 23 CpG sites (within CYP11A1, POR, CYB5A, HSD17B1, HSD17B2, HSD17B3, HSD17B6, HSD17B10, HSD17B12, CYP19A1, CYP21A2, and CYP11B2) and 4 DNA regions (within HSD17B2, HSD17B8, and HSD17B10) that were mostly hypomethylated. These abnormalities were partially sex- (1 CpG site) or age-dependent (7 CpG sites) and affected by glucocorticoid treatment (3 CpG sites). Finally, multivariable linear models identified robust associations of abnormal methylation of steroidogenic genes with shorter height further in time, at 4-year follow-up.

Conclusions: Children who have been critically ill show abnormal methylation within steroidogenic genes 2 years after PICU admission, which explained part of the stunted growth in height at 4-year follow-up. The abnormalities in DNA methylation may point to a long-term disturbance in the balance between active sex steroids and mineralocorticoids/glucocorticoids after paediatric critical illness, which requires further investigation.

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Abstract Image

小儿危重疾病后两年类固醇生成途径基因内的异常DNA甲基化与身高发育迟缓的关系
背景:与正常发育的健康儿童相比,前危重儿童在进入儿科重症监护病房(PICU) 2年后表现出表观遗传年龄减速,与身体相关的身高发育迟缓时间进一步延长2年。这在6岁以上的儿童中尤其明显。由于这个年龄大致对应于肾上腺素的开始和进一步的青春期发育,因此与内分泌通路激活的改变有关是合理的。我们假设,已入住PICU的儿童,性别和年龄依赖于类固醇激素合成或类固醇磺化/脱硫相关基因的DNA甲基化长期异常,可能因PICU内糖皮质激素治疗而加剧,这可能导致危重疾病后进一步发育迟缓。结果:在这一预先计划的多中心PEPaNIC-RCT及其随访的二次分析中,我们比较了2年随访的PICU前患者(n = 818)和性别和年龄相似的健康儿童(n = 392)口腔粘膜DNA中参与类固醇激素(醛固酮、皮质醇和性激素)生物合成的基因的甲基化状态和类固醇硫酸/去硫(Infinium HumanMethylation EPIC BeadChip)。结论:危重儿童在PICU入院后2年出现类固醇基因甲基化异常,这部分解释了4年随访时身高发育迟缓的原因。DNA甲基化异常可能提示小儿危重疾病后活性性类固醇和矿糖皮质激素/糖皮质激素之间的平衡长期失调,有待进一步研究。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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