title: A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants.
abstract: Tetrahydrobiopterin (BH(4)) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH(4) is tightly regulated by GTP-cyclohydrolase I feedback regulator (GFRP). Given the pivotal role of the serotonergic system in mood disorders and selective serotonin reuptake inhibitors (SSRIs) antidepressant function, we tested the hypothesis that GFRP gene (GCHFR) variants would modify response to antidepressants in subjects with major depression. Two single nucleotide polymorphisms (rs7164342 and rs7163862) in the GCHFR promoter were identified and occurred as two haplotypes (GA or TT). A multiple regression analysis revealed that homozygous individuals for the TT haplotype were less likely to respond to the SSRI fluoxetine than to the tricyclic antidepressant nortriptyline (P = 0.037). Moreover, the TT haplotype showed a reduced transcription rate in luciferase reporter gene assays, which may impact on BH(4)-mediated neurotransmitter production, thus suggesting a biological process through which GCHFR promoter variants might influence antidepressant response.
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand. pm303@bath.ac.uk
authors.forename: P C
authors.initials: PC
authors.lastname: McHugh
authors.forename: P R
authors.initials: PR
authors.lastname: Joyce
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.forename: M A
authors.initials: MA
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002986:Clinical Trials as Topic; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D019964:Mood Disorders / Q000188:drug therapy*; D009661:Nortriptyline / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012701:Serotonin / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D001708:Biopterins; D005473:Fluoxetine; D047908:Intracellular Signaling Peptides and Proteins; D009661:Nortriptyline; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C101092:GCHFR protein, human; C003402:sapropterin