Research articleAssociation of the TLR4 gene with depressive symptoms and antidepressant efficacy in major depressive disorder
Introduction
Major depressive disorder (MDD) is a common mental disorder characterized by significant and prolonged sadness, loss of interest, anhedonia, inability to concentrate, and memory deterioration. According to a report by WHO, MDD was found to have affected 322 million people and resulted in more than 50 million people with disabilities by 2015. MDD poses a serious threat to human health [1]. However, its etiology and pathogenesis are still unclear. In addition to abnormalities in neurotransmitters, neuroendocrine cells, an increasing amount of research has indicated that dysimmunity also plays a role in MDD. A meta-analysis found that compared to healthy people, the level of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), was significantly higher in patients with MDD [2]. Another meta-analysis similarly found that the levels of C-reactive protein (CRP), IL-3, IL-6, IL-12, and TNFα were significantly higher in patients with depression [3].
Toll-like receptors (TLRs) are one of the innate immune response pattern recognition receptors [4]. Some studies have found that TLRs were involved in the pathophysiology of MDD. As the TLRs family, TLR4 has received much attention in recent decades. TLR4 predominantly recognizes lipopolysaccharides (LPS) from gram-negative bacteria [5]. Both clinical studies and animal experiments have found abnormal expressions of TLR4. In clinical studies, Hung et al. [6] reported that TLR4 was an independent risk factor relating to the severity of MDD, while age, body mass index (BMI), gender, and TLR1-9 (except TLR4) were not associated with the severity of depression. Kéri et al. [7] reported that the level of TLR4 in depression patients was decreased by cognitive behavioral therapy (CBT). A postmortem study found that TLR4 expression was elevated in the dorsolateral prefrontal cortex (DLPFC) of depressed suicide victims compared to normal control [8]. In animal study, it was shown that the expression of TLR4 was enhanced in rats with acute restraint stress, at both the mRNA and protein levels [9]. The above research indicates that TLR4 plays an important role in the occurrence and development of MDD.
At present, the relationship between antidepressant efficacy and TLR4 is unclear. A study which analyzed the effect of antidepressants on TLRs mRNA levels in depressed patients showed that the mRNA expression level of TLR4 was increased in depressed patients. After 4 weeks of antidepressant treatment, the mRNA expression level of TLR4 was lower than normal [10]. Therefore, the purpose of this study is to analyze the association between TLR4 gene polymorphisms and depressive symptoms and antidepressant efficacy in patients with MDD.
Section snippets
Participants
The study consisted of 438 patients, with an average age of 34.51 ± 11.90. They were first-episode MDD and recruited from the First Hospital of Shanxi Medical University. The inclusion criteria was: 1) 18 ≤ age≤65, Han Chinese ; 2) HAMD17 score ≥17; 3) All patients were screened according to the diagnostic criteria for depression in the American Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) by two experienced psychiatrists. The exclusion criteria were: 1)
HWE and LD tests
The genotype distributions of the three TLR4 SNPs were in Hardy-Weinberg Equilibrium: rs1927911 (P = 0.783); rs11536889 (P = 0.619); and rs7873784 (P = 0.434). LD values were as follows: rs1927911-rs11536889 (r2 = 0.159, D’ = 0.919); rs1927911-rs7873784 (r2 = 0.026, D’ = 1); and rs11536889-rs7873784 (r2 = 0.128, D’ = 0.967).
Analysis of TLR4 gene polymorphisms and depressive symptoms
Genotype and allele frequencies of the TLR4 gene are shown in Table 2.
As shown in Table 3, Table 4, Table 5, Table 6, an association was observed between the HAMD17 total
Discussion
In this study, we analyzed whether there was an association between TLR4 gene polymorphisms and depressive symptoms and antidepressant efficacy. The results showed that three gene polymorphisms of TLR4 were associated with some depressive symptoms.
First, we found that anxiety (physical symptoms) and anxiety (somatic) were significantly associated with rs1927911 gene polymorphism. There was also a significant association between anxiety (psychological)、anxiety (physical symptoms) and rs7873784
Declaration of Competing Interest
The authors report no conflicts of interest in this work.
CRediT authorship contribution statement
Jizhi Wang: Data curation, Formal analysis, Investigation, Software, Writing - original draft. Chunxia Yang: Investigation, Funding acquisition, Resources, Validation, Writing - review & editing. Zhifen Liu: Investigation, Resources, Writing - review & editing. Xinxin Li: Investigation, Software, Writing - review & editing. Min Liu: Investigation, Formal analysis, Resources. Yanfang Wang: Investigation, Resources, Writing - review & editing. Kerang Zhang: Conceptualization, Funding acquisition,
Acknowledgments
This study was supported by the National Natural Science Youth Fund Project (81701345, 81601192), National key research and development program of China (2016YFC1307103), 136 Medical Rejuvenation Project of Shanxi Province, and Program for the Outstanding Innovative Teams of Higher Learning Institutions of Shanxi.
References (34)
- et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
Association between toll-like receptors expression and major depressive disorder
Psychiatry Res.
(2014) - et al.
Expression of Toll-Like Receptors in peripheral blood mononuclear cells and response to cognitive-behavioral therapy in major depressive disorder
Brain Behav. Immun.
(2014) - et al.
Toll-like receptors in the depressed and suicide brain
J. Psychiatr. Res.
(2014) - et al.
Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study
J. Psychiatr. Res.
(2017) - et al.
Outcomes of 1014 naturalistically treated inpatients with major depressive episode
Eur. Neuropsychopharmacol.
(2010) - et al.
A genetic epidemiologic perspective on comorbidity of depression and anxiety
Child Adolesc. Psychiatr. Clin. N. Am.
(2005) - et al.
Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: the POWER study
Biol. Psychiatry
(2008) - et al.
Interleukin-1 receptor null mutant mice show decreased anxiety-like behavior and enhanced fear memory
Neurosci. Lett.
(2009) - et al.
Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats
Psychoneuroendocrinology
(1999)
Toll-like receptor-4 regulates anxiety-like behavior and DARPP-32 phosphorylation
Brain Behav. Immun.
Toll-like receptor signaling in neural plasticity and disease
Trends Neurosci.
Low serum brain-derived neurotrophic factor is associated with suicidal ideation in major depressive disorder
Psychiatry Res.
Interleukin (IL)-8 polymorphisms contribute in suicide behavior
Cytokine
Cognitive impairment in major depression
Eur. J. Pharmacol.
Psychomotor retardation is a scar of past depressive episodes, revealed by simple cognitive tests
Eur. Neuropsychopharmacol.
Evidence for continuing neuropsychological impairments in depression
J. Affect. Disord.
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