title: Histaminergic gene polymorphisms associated with sedation in clozapine-treated patients.
abstract: Sedation is a common adverse effect of clozapine treatment, which may be partly related to clozapine binding to histamine receptors in the central nervous system. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the histaminergic system are associated with sedation in clozapine-treated patients. The study population comprised 237 clozapine-treated, Finnish, Caucasian patients that were diagnosed with schizophrenia and 176 were genotyped using Illumina HumanCoreExome-12 BeadChip. Sedation levels were assessed using self-rating questions from the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The relationships between 55 different SNPs in the histaminergic system and adverse sedation effects were examined. SNPs were analyzed separately, and in groups, to formulate a genetic risk score (GRS). A permutation test was performed to avoid type I errors. Eight linked SNPs (r2= 1) in the HNMT gene were also associated with sedation according to the GLM, adjusted for age, gender and BMI (false-discovery-rate-adjusted p = 0.013). An association on a trend level between a GRS of four different SNPs (recessive histamine N-methyltransferase HNMT rs2737385, additive histamine receptor H1rs1552498, dominant HRH1 rs17034063 and recessive amine oxidase, copper containing 1 AOC1 rs6977381) and sedation was found (permuted p-value = 0.066) in a generalized linear model (GLM) incorporating age, gender and body mass index (BMI; adjusted R2= 0.22). Polymorphisms in genes encoding histamine receptors or enzymes related to histamine metabolism may explain individual variation in sedative effects experienced during clozapine treatment.
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland; Seinäjoki Hospital District, Department of Psychiatry, Seinäjoki, Finland. Electronic address: asolismaa@gmail.com.
authors.forename: Anssi
authors.initials: A
authors.lastname: Solismaa
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland; Seinäjoki Hospital District, Department of Psychiatry, Seinäjoki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kampman
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.affiliation: Tampere University Hospital, Department of Psychiatry, Tampere, Finland.
authors.forename: Niko
authors.initials: N
authors.lastname: Seppälä
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Viikki
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Mononen
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland; Tampere University Hospital, Department of Psychiatry, Tampere, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Leinonen
mesh_terms: D000328:Adult; D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics; D014150:Antipsychotic Agents / Q000009:adverse effects*; D016009:Chi-Square Distribution; D003024:Clozapine / Q000009:adverse effects*; D016292:Procedural Sedation; D005260:Female; D005387:Finland; D005838:Genotype; D006637:Histamine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome / Q000209:etiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011968:Receptors, Histamine / Q000235:genetics*; D012044:Regression Analysis; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D014150:Antipsychotic Agents; D011968:Receptors, Histamine; D006631:Amine Oxidase (Copper-Containing); D006637:Histamine N-Methyltransferase; D003024:Clozapine
keywords: Adverse events; Antipsychotic agents; Clozapine; Histamine; Sedation; Single nucleotide polymorphism