Common genetic variations in human brain-specific tryptophan hydroxylase-2 and response to antidepressant treatment.
OBJECTIVE
Genetic variability within the serotoninergic system may predict the response to antidepressant drugs. Several polymorphisms in the gene coding for the brain-specific tryptophan hydroxylase (TPH2) have been associated with susceptibility to psychiatric diseases. In this study, we analyzed the correlation between TPH2 polymorphisms and response to antidepressant drugs.


METHODS
The study included 182 patients who received drug treatment for major depression. To assess the variability in the TPH2 gene, four single nucleotide polymorphisms (SNPs) tagging the common TPH2 haplotypes and six SNPs medically relevant according to data from other studies were analyzed in a multiplex single base primer extension reaction.


RESULTS
Two SNPs, rs10897346 and rs1487278, were significantly associated with response to therapy (P=0.003 and 0.007). The rs10897346 variant showed the highest predictive values with carriers of null C alleles showing a 2.6-fold increased risk (95% confidence interval 1.4-4.8) for nonresponse compared with the others. The effect was found in all major types of antidepressant medications administered in this study and was statistically significant in the subgroup on selective serotonin reuptake inhibitors. Multiple logistic regression analyses confirmed the rs10879346 polymorphism as an independent predictor of the antidepressant response (odds ratio: 3.86; 1.75-8.55, P=0.0008). The therapeutically relevant variant rs10897346 is completely linked with the functional Pro312Pro polymorphism, which is known to affect TPH2 expression and may influence serotonin synthesis in the brain.


CONCLUSIONS
The polymorphisms rs10897346 and Pro312Pro in the TPH2 gene might play an important role for TPH2 expression and antidepressant drug response.
Tzvetkov
Mladen Vassilev
MV
Department of Clinical Pharmacology, Georg-August University, Göttingen, Germany. mtzvetk@gwdg.de
Brockmöller
Jürgen
J
Roots
Ivar
I
Kirchheiner
Julia
J
D000928:Antidepressive Agents / Q000494:pharmacology*; D001483:Base Sequence; D001921:Brain / Q000201:enzymology*; D017931:DNA Primers / Q000235:genetics; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D014365:Tryptophan Hydroxylase / Q000235:genetics*
D000928:Antidepressive Agents; D017931:DNA Primers; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase