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

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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.

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Acknowledgements

Research performed under the young-investigator “ADHD-sythe” project (“under 40” call 2007) and the EU “NeuroGenMRI” project (ERAnet “PrioMedChild”), both from Italian Ministry of Health (for Italian partner, to W. A.); in part, supported under Grant Agreements ref. 278367 “EMTICS—European Multicentre Tics In Children Studies” and ref. 603016 “MATRICS—Multidisciplinary Approaches to Translational Research In Conduct Syndromes” by European Seventh Framework Programme (FP7) 2007–2013 (for Italian partner, to G. L.). We acknowledge Dr Nadia Francia and Dr Viola Cardia for their precious help with all management and patenting issues. There are only two items for potential conflict of interest to be disclosed: (1) Adriani W, Laviola G, Pascale E, D’Addario C “Metodo Per Determinare Il Deficit Di Attenzione Con Iperattività (Method to determine attention deficit and hyperactivity disorder)”; Patent Application, deposit in ITALY at No. 102016000129938 (22-DECEMBER-2016). (2) Granstrem O, Adriani W, Laviola G, Porfirio MC, Curatolo P “Biomarkers for validation of A.D.H.D. diagnosis and monitoring of therapy efficacy”; Full Patent No. PN810701WO; Int.l Application No. PCT/EP2013/066845; Publication number WO/2014/023852 (10-AUGUST-2013).

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

    Walter Adriani, Emilia Romano & Giovanni Laviola

  2. Faculty of Psychology, Università Telematica Internazionale “Uninettuno”, Rome, Italy

    Walter Adriani & Luca Cerniglia

  3. Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy

    Mariangela Pucci & Claudio D’Addario

  4. Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Rome, Italy

    Esterina Pascale

  5. Dynamic and Clinical Psychology Department, “Sapienza” University of Rome, Rome, Italy

    Silvia Cimino & Renata Tambelli

  6. Pediatric Neurology Unit, Department of System Medicine, “Tor Vergata” University of Rome, Rome, Italy

    Paolo Curatolo

  7. NBioService Ltd, Saint-Petersburg, Russia

    Oleg Granstrem

  8. Department of Medicine, “Campus Bio-Medico” University of Rome, Rome, Italy

    Mauro Maccarrone

  9. European Center for Brain Research, IRCCS “Santa Lucia”, Rome, Italy

    Mauro Maccarrone & Claudio D’Addario

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  1. Walter Adriani
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Adriani, W., Romano, E., Pucci, M. et al. Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity. Eur Child Adolesc Psychiatry 27, 241–252 (2018). https://doi.org/10.1007/s00787-017-1040-9

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