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 ¼ 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.

Valproic acid exposure leads to upregulation and increased promoter histone acetylation of sepiapterin reductase in a serotonergic cell line

“…We also observed association between promoter variants of the Spr gene and susceptibility to mood disorders as well as to antidepressant treatment response (McHugh et al, 2009). A similar analysis of promoter variants for another enzyme in the BH4 biosynthetic pathway, GTPcyclohydrolase I feedback regulator (GFRP), also suggested an association with antidepressant responses (McHugh et al, 2011).…”

Genome-wide Expression Profiling of Human Lymphoblastoid Cell Lines Identifies CHL1 as a Putative SSRI Antidepressant Response Biomarker

“…n Advantages of genome-wide expression profiling Earlier attempts to identify genetic biomarkers for antidepressant drug response have focused on DNA polymorphism using either the candidate gene approach, most notably serotoninrelated genes such as the serotonin transporter SLC6A4 [7][8] and serotonin receptors or other candidate genes related to serotonin or corticotrophin signaling [11][12][13][14]. None of these genes studied by the candidate approach were among those identified in the current study.…”

“…However, the translation of these findings into clinical practice has been hampered by the problem of negative replication, and a recent meta-ana lysis of all studies on the serotonin transporter polymorphism has demonstrated that the effect is not significant [10]. Similarly, candidate gene studies on SSRI efficacy in major depression have examined other genes as predictors for SSRI response, including the HTR2A serotonin receptor [11], genes regulating the corticotropin-releasing factor system [12], the GTP-cyclohydrolase I feedback regulator gene [13] and G(a)i2 [14], However, to date the evident impact on drug response is not sufficient for using these genes as biomarkers for individual response prediction.…”

Repurposing of Tranilast for Potential Neuropathic Pain Treatment by Inhibition of Sepiapterin Reductase in the BH4 Pathway

“…Tetrahydrobiopterin pathway, depicting key regions of SPR activity, and the various techniques performed to assess this under treatment with tranilast (figure amended from ref (33)).…”