Elsevier

Neuroscience Letters

Volume 736, 25 September 2020, 135292
Neuroscience Letters

Research article
Association of the TLR4 gene with depressive symptoms and antidepressant efficacy in major depressive disorder

https://doi.org/10.1016/j.neulet.2020.135292Get rights and content

Highlights

  • First-episode patients with TLR4SNP rs1927911-GG had higher scores of anxiety (physical symptoms) and anxiety (somatic).

  • First-episode patients with TLR4SNP rs11536889-GG and rs11536889-G had lower suicide scores and higher psychomotor retardation scores.

  • First-episode patients with TLR4SNP rs7873784-G had higher scores of anxiety (physical symptoms) and anxiety (psychological).

Abstract

At present, the etiology and pathogenesis of major depressive disorder(MDD) are still unclear. Some studies have shown that toll-like receptor 4 may play an important role in MDD. However, little is currently known about the association between TLR4 single gene polymorphisms (SNPs) and depressive symptoms and antidepressant efficacy.The aim of this study is to analyze whether TLR4 SNPs are associated with depressive symptoms and antidepressant efficacy. The study consisted of 438 patients with first-episode depression. We analyzed three TLR4 SNPs (rs1927911, rs11536889, and rs7873784) and obtained the baseline and 6-week scores using the 17-item Hamilton Depression Rating Scale (HAMD17) and its five-factor model. Allelic and genotypic association tests between TLR4 SNPs and HAMD17 total and cluster scores were performed with UNPHASED, while chi-square tests to analyze the association between TLR4 SNPs and response to antidepressants were performed with SPSS. Patients with the rs1927911-GG genotype exhibited higher scores of anxiety (physical symptoms) and anxiety (somatic). Patients with rs1927911-G also exhibited higher anxiety (physical symptoms) and anxiety (somatic) scores. Patients with rs11536889-GG had significantly lower suicide scores and higher psychomotor retardation scores. Patients with rs11536889-G also had significantly lower suicide scores and higher psychomotor retardation scores. Patients with rs7873784-G had higher anxiety (physical symptoms) and anxiety (psychological) scores. There was no significant difference between antidepressant efficacy and TLR4 gene polymorphisms. These findings provide evidence that TLR4 plays an important role in anxiety, suicide, and other symptoms in patients with MDD. No relationship was found between TLR4 gene polymorphisms and antidepressant efficacy in this study. Further research is needed on gene polymorphisms and the expression of TLR4 in patients with MDD.

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.

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