title: Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine.
abstract: Animal models suggest that the casein kinase 1 epsilon gene (Csnk1e) contributes to variability in stimulant response. Csnk1e is a key component in the Darpp-32 (Dopamine-And-cAMP-Regulated-Phosphoprotein-32 kDa) second messenger pathway and has been implicated in previous pharmacological and pharmacogenetic studies in mice. Mice bred for methamphetamine sensitivity showed linkage to the region of chromosome 15 that contains Csnk1e and also showed a 10-fold increase in expression of Csnk1e. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNK1E region and subjective response to placebo, 10, or 20 mg of oral D-amphetamine. Repeated-measures ANOVA was used to analyze interactions between genotype and drug response. The primary outcome measure, subjects' ratings of whether they felt a drug effect (Drug Effects Questionnaire (DEQ)), revealed a significant effect (p=0.010) at one single-nucleotide polymorphism (rs135745). Subjects with more copies of the rs135745 C allele were more sensitive to the low dose of D-amphetamine (p=0.001), which corresponded to a leftward shift in the dose-response curve. These findings demonstrate the successful translation of pharmacogenetic results from mice to humans.
authors.affiliation: Institute of Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60637, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Veenstra-VanderWeele
authors.forename: Asfia
authors.initials: A
authors.lastname: Qaadir
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Palmer
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Harriet
authors.initials: H
authors.lastname: de Wit
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D048149:Casein Kinase 1 epsilon / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D018592:Cross-Over Studies; D003913:Dextroamphetamine / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D051379:Mice; D023421:Models, Animal; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011795:Surveys and Questionnaires
chemical_list: D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497928:PPP1R1B protein, human; D048149:Casein Kinase 1 epsilon; D003913:Dextroamphetamine