Association between single nucleotide polymorphisms of TPH1
and TPH2 genes, and depressive disorders
, Piotr Czarny
, Ewelina Synowiec
, Michał Bijak
, Katarzyna Białek
, Piotr Galecki
, Janusz Szemraj
, Tomasz Sliwinski
Laboratory of Medical Genetics, Department of Molecular Genetics, Faculty of Biology and Environmental Protection,
University of Lodz, Lodz, Poland
Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
Received: August 23, 2017; Accepted: October 16, 2017
Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan
hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to conﬁrm the association between the
presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected:
c.804-7C>A (rs10488682), c.-1668T>A (rs623580), c.803+221C>A (rs1800532), c.-173A>T (rs1799913)—TPH1, c.-1449C>A (rs7963803),
and c.-844G>T (rs4570625)—TPH2. A total of 510 DNA samples (230 controls and 280 patients) were genotyped using TaqMan probes.
Among the studied polymoorphisms, the G/G genotype and G allele of c.804-7C>A—TPH1, the T/T homozygote of c.803+221C>A—TPH1, the
A/A genotype and A allele of c.1668T>A—TPH1, the G/G homozygote and G allele of c.-844G>T—TPH2, and the C/A heterozygote and A allele
of c.-1449C>A—TPH2 were associated with the occurrence of depression. However, the T/T homozygote of c.-1668T>A—TPH1, the G/T
heterozygote and T allele of c.-844G>T—TPH2, and the C/C homozygote and C allele of c.-1449C>A—TPH2 decreased the risk of development
of depressive disorders. Each of the studied polymorphisms modulated the risk of depression for selected genotypes and alleles. These results
support the hypothesis regarding the involvement of the pathway in the pathogenesis of depression.
tryptophan catabolites pathways
single nucleotide polymorphism
Although the pathogenesis of depression (depressive disorder—DD)
is not fully understood, studies suggest that disturbances in the TRY-
CATs pathway may play a key role in the development of this disease.
A reduced level of tryptophan in plasma may lead to mood disorders
in patients [1, 2]. Moreover, increased plasma levels of harmful tryp-
tophan metabolites—i.e. kynurenine, xanthurenic acid and quinolinic
acid—were found in depressed patients [1, 2]. Quinolinic acid may
cause the destruction of postsynaptic structures and neurons via
apoptosis of hippocampal cells and selective necrosis of granular
cells. Additionally, it reduces the levels of dopamine, choline and c-
aminobutyric acid (GABA) [3–5]. On the other hand, studies showed
that some tryptophan metabolites, for example kynurenic acid, may
exhibit neuroprotective and antidepressant properties .
Recent ﬁndings have revealed that the patients with DD are char-
acterized by greater activity of 2,3-dioxygenase tryptophan (TDO) and
2,3-dioxygenase indoleamine (IDO) as compared to healthy volun-
teers. Both are rate-limiting enzymes in tryptophan metabolism .
IDO/TDO converts tryptophan into kynurenine, which may be later
metabolized into neurotoxic compounds, such as quinolinic acid. As a
result, depressed patients are characterized by an increased kynure-
nine/tryptophan ratio and decreased serotonin/tryptophan ratio [1, 2].
Additionally, toxic TRYCATs can bring about increased production
of reactive oxygen species (ROS). For example, 3-hydroxykynurenine
can induce neuronal apoptosis via overproduction of ROS . More-
over, kynurenine may penetrate the blood–brain barrier and exhibits
toxic effects in the brain. As a consequence, it can lead to spreading
cortical and subcortical atrophy .
Decreased levels of serotonin (5-TH) or its receptors are also
associated with depressed mood . This neurotransmitter is synthe-
sized by tryptophan hydroxylase (TPH) . TPH is an enzyme which
*Correspondence to: Tomasz SLIWINSKI
ª 2018 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1778-1791