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


Reference:

McHugh, P. C., Joyce, P. R., Deng, X. and Kennedy, M. A., 2011. A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants. Pharmacogenomics Journal, 11 (3), pp. 207-213.

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Official URL:

http://dx.doi.org/10.1038/tpj.2010.23

Abstract

Tetrahydrobiopterin (BH4) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH4 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 BH4-mediated neurotransmitter production, thus suggesting a biological process through which GCHFR promoter variants might influence antidepressant response.

Details

Item Type Articles
CreatorsMcHugh, P. C., Joyce, P. R., Deng, X. and Kennedy, M. A.
DOI10.1038/tpj.2010.23
Uncontrolled Keywordsssris, neurotransmitters, pharmacogenetics, tetrahydrobiopterin
DepartmentsFaculty of Science > Biology & Biochemistry
RefereedYes
StatusPublished
ID Code24123

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