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注意缺陷多动障碍的诊断与治疗监测潜力:与基因型和自身免疫相互作用的新型表观遗传生物标志物。

Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity.

机构信息

Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Building 19 Floor D Room 5, viale Regina Elena 299, 00161, Rome, Italy.

Faculty of Psychology, Università Telematica Internazionale "Uninettuno", Rome, Italy.

出版信息

Eur Child Adolesc Psychiatry. 2018 Feb;27(2):241-252. doi: 10.1007/s00787-017-1040-9. Epub 2017 Aug 18.

Abstract

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.

摘要

鉴于需要易于获取的生物标志物,我们评估了注意缺陷多动障碍(ADHD)儿童中编码人类多巴胺转运蛋白(DAT)的 SLC6A3 基因 5'-非翻译区(UTR)的表观遗传状态。我们分析了 30 名符合 DSM-IV-TR 标准的 ADHD 儿童的口腔拭子和血清,根据严重程度进行治疗分配。分析了六个选定 CpG 位点(包括一个 CGGCGGCGG 和一个 CGCG 基序)的甲基化水平,单独或与针对多巴胺转运蛋白(DAT aAbs)的自身抗体的血清滴度相结合,与 CGAS 评分(由临床医生)和 Conners 量表(由父母)进行相关性分析,在招募时和 6 周后收集。此外,我们还对 DAT 基因型进行了特征描述,即基因 3'-UTR 的可变数目串联重复(VNTR)多态性。与对照组健康儿童相比,ADHD 患者的 DAT 甲基化水平显著降低。在至少携带一个 DAT 9 等位基因(DAT 9/x)的患者中,CpG2 和/或 CpG6 位置的甲基化与恢复相关,这从 CGAS 评分的变化以及 Conners 量表的变化(“注意力不集中”和“多动”子量表)可以看出。此外,CpG1 位置的高甲基化表示严重程度,特别是对于携带 DAT 10/10 基因型的患者。有趣的是,高 DAT-aAbs 血清滴度似乎证实了 CpG1 与 CpG2/CpG6 水平升高的指示,同样表示 DAT 10/10 与 9/x 患者的严重程度与恢复。这些特征表明,DAT 5'UTR 表观遗传学加上血清 aAbs 可以作为合适的生物标志物,用于确认 ADHD 的诊断和/或预测治疗效果。

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