| Popis: |
Marta H Hernandez1,2 *, Valentin Bote3 *, Alexandre Serra-LLovich,1 Marc Cendros,1,4 Juliana Salazar,5 Conxita Mestres,2 Silvina Guijarro,3 Aida Alvarez,3 Cristina Lamborena,3 Iria Mendez,3 Bernardo Sanchez,3 Amaia Hervas,3 Maria J Arranz1,2 1Research Laboratory Unit, Fundació Docència i Recerca Mútua Terrassa, Terrassa, Spain; 2School of Health Sciences Blanquerna, University Ramon Llull, Barcelona, Spain; 3Department of Child and Adolescent Psychiatry, Hospital Universitari Mútua Terrassa, Terrassa, Spain; 4EUGENOMIC Genómica y Farmacogenética, Barcelona, Spain; 5Translational Medical Oncology Laboratory, Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain*These authors contributed equally to this workCorrespondence: Maria J Arranz, Research Laboratory Unit, Fundació Docència i Recerca Mútua Terrassa, c/Sant Antoni, 19, Terrassa, 08221, Spain, Tel +34 937 36 50 50, Fax +34 93 736 50 21, Email mjarranz@mutuaterrassa.esPurpose: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40â 70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety.Patients and Methods: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype.Results: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05).Conclusion: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.Keywords: CES1, SLC6A2, autistic spectrum disorders, ASD, methylphenidate, attention deficit hyperactivity disorders, ADHD |
