A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

P C McHugh, P R Joyce, X Deng, M A Kennedy

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

LanguageEnglish
Pages207-13
Number of pages7
JournalPharmacogenomics Journal
Volume11
Issue number3
DOIs
Publication statusPublished - Jun 2011
Externally publishedYes

Fingerprint

GTP Cyclohydrolase
Serotonin Uptake Inhibitors
Regulator Genes
Haplotypes
Antidepressive Agents
Neurotransmitter Agents
Nortriptyline
Biological Phenomena
Serotonergic Neurons
Tricyclic Antidepressive Agents
Fluoxetine
Luciferases
Mood Disorders
Reporter Genes
Single Nucleotide Polymorphism
Serotonin
Regression Analysis
Depression
Genes

Cite this

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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.",
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A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants. / McHugh, P C; Joyce, P R; Deng, X; Kennedy, M A.

In: Pharmacogenomics Journal, Vol. 11, No. 3, 06.2011, p. 207-13.

Research output: Contribution to journalArticle

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