title: Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine.
abstract: The serotonin 1B receptor (5-HT1B) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants.
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gassó
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rodríguez
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Blázquez
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Monteagudo
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Boloc
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Plana
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Amalia
authors.initials: A
authors.lastname: Lafuente
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Spain; Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Lázaro
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Clinical Pharmacology Department, Hospital Clinic de Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: JAARNAIZ@clinic.ub.es.
authors.forename: Joan Albert
authors.initials: JA
authors.lastname: Arnaiz
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain. Electronic address: sergimash@ub.edu.
authors.forename: Sergi
authors.initials: S
authors.lastname: Mas
mesh_terms: D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000178:diet therapy / Q000235:genetics; D002648:Child; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics*; D013223:Statistics as Topic; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; C470302:HTR1B protein, human; D044302:Receptor, Serotonin, 5-HT1B; D005473:Fluoxetine
keywords: Children; Fluoxetine; HTR1B; Methylation; Pharmacogenetics; Polymorphism