Ассоциация генов воспалительных цитокинов с депрессией: History
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Depressive disorders are a heterogeneous group of diseases. The etiology, precise pathophysiological mechanisms, response to treatment, and outcome of depressive disorders are still poorly understood. The cytokine hypothesis of depression proposes that pro-inflammatory cytokines acting as neuromodulators are a key factor mediating behavioral, neuroendocrine, and neurochemical changes in this disease.

  • cytokines
  • SNP
  • depressive disorder
  • mental disorders
  • neuroinflammation
  • polymorphisms

1. Introduction

Mental disorders are considered multifactorial diseases. They manifest as clinically significant impairments in cognition, emotion regulation, and behavior and can range from mild to sever [1]. Serious mental illnesses or severe mental illnesses limit one or more major life activities, interfere with quality of life, and can lead to disability. Mental disorders involve general neurobiological processes, such as disruption of the nervous tissue and the blood-brain barrier, autoimmune processes, and neurodegenerative processes. Glial and neuronal changes, metabolic changes in cellular processes, and molecular mechanisms lead to impaired expression of neurospecific proteins. The mechanism of immune response is manifested in changes in levels of hormones and neuromodulators, disruption of psychoendocrine processes, and neurotransmitter systems. Studies of the pathophysiology of severe mental disorders have traditionally emphasized dysregulation of the glutamatergic and monoaminergic systems. However, the mechanisms that cause these neurotransmitter abnormalities are still not clear. Accumulating evidence suggests the interaction of neuroinflammation with the serotonergic, dopaminergic, and glutamatergic systems and the pathogenic role of neuroinflammation in mental disorders [2,3,4,5].
Neuroinflammation includes changes in microglia, astrocytes, cytokines, and chemokines in the central nervous system. There are over 300 cytokines, including chemokines, interleukins, interferons, and growth factors, which play an important role in regulating immune and inflammatory responses [6]. Inflammation plays a role in psychiatric disorders such as bipolar disorder (BD) [7], major depressive disorder (MDD) [8], substance use disorder [9], schizophrenia (SCZ) [10,11,12] and post-traumatic stress disorder [13]. Emerging research suggests that genetic vulnerability could be involved in immune activation in psychiatric disorders [14,15].
The results of bidirectional Mendelian randomization analysis of genome-wide association studies (GWAS) indicate the causative relationship between inflammatory regulators and the risk of mental disorders including MDD, SCZ, and BD [16]. However, the most replicated and relevant genetic variants of cytokines include polymorphisms in the IL1B, IL6, and IL10 genes [17,18]. Many studies have revealed dysregulation of the concentration of genetically associated cytokines in the blood of patients with MDD [19,20,21], BD [22], and SCZ [23,24]. There is evidence that genetic polymorphisms affect the expression of pro-inflammatory cytokine genes [25]. Dysregulation of cytokine gene expression has been identified in mental disorders [26]. Nevertheless, the results of studies of the associations of cytokine gene variants with severe mental disorders are heterogeneous and require systematization.

2. Depression Is Associated with Polymorphic Variants of Cytokines Genes

Identifying a common genetic substrate for depression and immune activation will help unravel the link between neuroinflammation and depression. This section describes the association of inflammatory cytokine genes with depression, and polymorphisms that increase or decrease this association. Current research indicates that individual polymorphisms play a role in susceptibility to depression and outcome.
Gene polymorphisms encoding cytokines and their receptors can influence their functional activity. Available data on the genetic association of single-nucleotide polymorphisms (SNPs) in cytokines and their receptor genes with depression is presented in Table 1.
Table 1. Association of cytokine and their receptor gene polymorphisms with depressive disorders.
Research Analyzed Polymorphisms Sample Results
Kim et al. (2017) [29] TNFA: rs1799724 (−850C/T; −308G/A);
IL1B: rs16944 (−511C/T), +3953C/T
286 patients with PSD −511C/T polymorphism was associated with primary depression and PSD at 2 weeks; higher TNF-α levels were associated with PSD at 2 weeks in in patients carried −850T allele.
Tartter et al. (2015) [30] IL6: rs1800795 (−174G/C);
IL1B: rs16944 (−511C/T);
TNF: rs1800629 (−308G/A)
444 young adults whose exposure to chronic stress in the past 6 months; Australian cohort Patients with the −174G allele had fewer depressive symptoms after interpersonal stress compared with CC homozygotes with equal exposure to interpersonal stress. The −511C allele in IL1B was associated with more severe depression after chronic interpersonal stress compared with TT homozygotes.
Lezheiko et al. (2018) [31] IL1B: rs16944 (−511T/C);
TNFA: rs1800629 (−308A/G)
139 patients with depression vs. 530 HS; Russian cohort The −511T/C and −308A/G polymorphisms were associated with depression; CC genotype and GG genotype are the risk factors of depression.
McQuaid et al. (2019) [32] IL1B: rs16944;
IL6: rs1800795;
TNFA: rs1800629
475 university students Depressive symptoms were higher among individuals who experienced childhood adversity with the GG genotype of the IL1B rs16944.
Kovacs et al. (2016) [33] IL1B: rs16944, rs1143643 1053 persons; Hungarian cohort The rs16944*A allele was associated with childhood adversity increasing anxiety and depressive symptoms. The A allele of rs1143643 demonstrated protective effect against depressive symptoms after recent life stress.
Bialek et al. (2020) [18] IL1B: rs1143623 (−1560G/C), rs1143627 (−118C/T);
IL1A: rs17561 (c.340G/T);
TNFA: rs1799964 (−1211T/C), rs1800629
(−488G/A)
270 patients with depression vs. 231 HS; Polish cohort It was shown an association between the T allele and the TT genotype of rs1799964 TNFA and low effectiveness of pharmacotherapy; the C allele and CT genotype were associated with good response to therapy.
Carryer of GC and CC genotypes of rs1143623 IL1B showed varying levels of disease severity ccording to the HDRS. The combined genotypes of rs1143627–rs17561, rs1143627–rs1799964 and rs1143623–rs1799964, decreased the risk of depression occurrence, rs1143627–rs1800629 increased the risk.
Kang et al. (2017) [34] IL1B: rs16944 (−511C/T), +3953C/T 969 patients at 2 weeks after ACS, 711—at 1 year later Depression during the acute ACS was associated with the −511T allele and the IL-1β levels. There was no association with depression in chronic ACS. There was no association with depression in the acute or chronic phase and the +3953C/T genotype.
Draganov et al. (2019) [35] 41 SNPs in IL1B, IL2, IL6, IL6R, IL10, IL18, TNFA, IFNG 153 patients with MDD Polymorphic variant rs1143643 of IL1B was associated with MSM scores. Allelic distribution of rs57569414 IL6R demonstrates a trend to significance with MSM scores. Combinations of alleles of IL1B and IL10 were associated with response to treatment.
Kim et al. (2013) [36] TNFA: rs1800629 (−308G/A);
IL10: rs1800896 (−1082A/G);
IFNG: rs2430561 (+874T/A)
301 patients with MDD (204 attempted suicide, 97 not attempted suicide); Korean cohort Among patients with MDD the TNFA −308GG genotype was associated with an increased risk of suicide; IL10-1082A/G were not associated with that risk.
Tsai et al. (2023) [37] GWAS involving 684,616 SNPs 65 patients with TRD; Chinese cohort Two SNPs (rs2540315 and rs75746675) in IL1R1 were associated with a rapid (within 240 min) antidepressant effect of ketamine infusion in patients with TRD.
Kim et al. (2013) [38] TNFA: rs1799724 (−850C/T);
IL1B: rs16944 (−511C/T), +3953C/T;
IL6: rs1800795 (−174G/C);
IL8: −251T/A;
IL4: +33T/C;
IL10: rs1800896 (−1082A/G)
309 women with breast cancer at one week after surgery, 244 (79%)—at one year later. IL1B-511TT was associated with depression at one week after surgery with breast cancer and persistent depression at one year follow-up.
Luckhoff et al. (2016) [39] TNFA: rs1800629 (−308G/A) 94 patients with MDD vs. 97 HS; South African cohort The rs1800629*A-allele in TNFA was associated with early-onset of MDD.
Lu et al. (2023) [40] IL6: rs1800795; rs1800796 114 patients with depression vs. 110 HS; Han Chinese cohort The CC genotype and the C allele of rs1800796 were associated with depression.
Golimbet et al. (2017) [41] IL4: −589C/T;
IL6: rs1800795 (−174G/C);
TNFA: rs1800629 (−308G/A);
CRP: −717A/G
78 male CHD patients with depression; 91—without depression; 127 HS; Russian cohort The IL6-174G/C was associated with depression comorbid to CHD. The IL4-589C/T was associated with CHD. No association between the TNFA-308G/A and the CRP-717A/G with depression in CHD.
Kovacs et al. (2016) [42] IL6 : rs1800795 1053 volunteers; Hungarian cohort The IL6 rs1800795 in common with various stressors increases the risk of depression and has a greater impact measured by the ZSDS symptoms.
Gal et al (2023) [43] IL6 : rs1800795 UK Biobank,
n = 277 501
The rs1800795 was associated with recent stress on current depressive symptoms and lifetime depression.
Udina et al. (2013) [44] IL6 : rs1800795 385 patients with chronic hepatitis; Caucasian cohort The rs1800795 IL6 increases the risk of induced by IFN depression and anxiety. It was associated with fatigue rates in patients with chronic hepatitis C before treatment.
Zhang et al. (2016) [45] IL6 : 1800797 772 patients with MDD vs. 759 HS; Han Chinese cohort Association between rs1800797 and the risk of MDD.
Maciukiewicz et al. (2015) [46] Twenty SNPs in IL1B, IL2, IL6, TSPO and BDNF MDD patients treated with duloxetine (n = 215) or placebo (n = 235) Association IL6 (−63G/A, rs2066992; +1984T/G, rs10242595) with response to duloxetine therapy in MDD patients. IL6 rs2066992 and rs10242595 were associated with duloxetine response. The rs2066992 was associated with placebo response.
Khandaker at al. (2018) [47] IL6R: rs2228145 (Asp358Ala) 9912 unselected participants from the ALSPAC birth cohort Asp358Ala was associated with a reduced risk of severe depression and/or psychosis. Asp358Ala was not associated with total depression score and with the risk factors related with inflammation, depression or psychosis.
Dunn et al. (2013) [48] 104 SNPs and haplotypes in 15 cytokine genes 167 oncology patients with prostate, breast, lung, or brain cancer and 85 of their FCs Significant associations of cytokine gene variants with trajectories of depressive symptoms in cancer patients and their FC have been identified. Two of these associations were in genes with anti-inflammatory functions (IL1R2, IL10), and one was with a gene with proinflammatory functions (TNFA).
Doong et al. (2015) [49] 82 SNPs in 15 genes of cytokine 398 breast cancer patients Significant associations between IL6 rs2069845, IL13 rs1295686, and TNFA rs18800610 with a symptom cluster of pain, sleep disturbance, fatigue and depression.
Santos et al. (2016) [50] IL18: rs1946518 (-607A/C), rs187238 (-137C/G) 80 MDD patients; Portuguese cohort IL18-607A/C and IL18-137C/G were associated with the effect of the AD therapy. Patients carrying CA or AA genotypes of -607A/C and patients carrying GC or CC genotypes of -137C/G were significantly more prone to relapse after therapy and present a significantly lower time to relapse.
Sandoval-Carrillo et al. (2018) [51] TNFA: rs1799724 (-857C/T), rs1800629 (-308G/A), rs361525 (-238G/A) 153 pregnant women with depression vs. 177 HS The −857CT genotype increased the risk for depression. The −238GA genotype reduced the risk. No association between the −308G/A polymorphism and depression risk. The C857-G308-A238 haplotype was associated with a decrease of depression risk.
Saad et al. (2014) [52] 82 SNPs in 15 cytokine genes 155 patients with resilient and 180 patients with subsyndromal depressive symptom classes In patients with breast cancer variation in three cytokine genes IFNGR1 rs937626, IL6 rs2069840, TNFA rs1799964, predicted membership in the Subsyndromal versus the Resilient class as well as age and functional status.
Bialek et al. (2020) [53] TGFB1: rs1800469 (g.41354391A/G);
IRF: rs2070729 (g.132484229C/A);
PTGS2: rs5275 (186643058A/G);
PTGS2: rs4648308 (g.186640617C/T);
TGF-α: rs2166975 (g.70677994G/A);
IKBKB: rs5029748 (g.42140549G/T).
80 patients with depression vs. 180 HS The AG genotype of rs2166975 TGFA was associated with an increased risk of depression, the GG genotype reduced the risk. The AG genotype and G allele of the rs2166975 TGFA was associated with increased risk of depression development in men. Genotype rs1800469*AA of TGFB1 was associated with earlier age of onset of the disease, GG genotype increased severity of the depressive episode.
Mihailova et al. (2016) [54] TNFA , TGFB , IL10 , IL6 , IFNG 80 patients with depression vs. 50 HS; Bulgarian cohort The TGFB + 869TT genotype (rs1800470) prevailed in patients compared with HS. The TT-GC combined genotype (+869T/C, +915G/C) was associated with disease recurrence.
Abbreviations: PSD: post-stroke depression; HS: healthy subjects; HDRS: Hamilton Depression Rating Scale; ACS: acute coronary syndrome; MDD: major depressive disorder; MSM: Mausdley Staging Method; SNP: single nucleotide polymorphism; GWAS: genome-wide association study; TRD: treatment-resistant depression; CHD: coronary heart disease; ZSDS: Zung Self-rating Depression Scale; FCs: Family Caregivers; AD: antidepressant therapy.
The IL1B gene is the most extensively examined in the field of psychiatry among the cytokine gene polymorphisms. Genetic polymorphisms in the IL1B gene have been well studied in depression. IL-1β has been implicated in the pathophysiology of major depression. Recent studies have identified the involvement of the IL1B gene in depression [29,34]. Among polymorphisms in the IL1B gene, more attention is given to the −511C/T (rs16944). The −511C allele in IL1B was associated with higher ILB expression [30] and higher IL-1β levels. The −511C/T polymorphism was associated with a depression [31,34]. The risk variant for depression was the CC genotype (p = 0.001, OR = 1.9 CI 1.3–2.7) [31]. There is much research dedicated to studying the contribution of IL1B-511C/T in the pathogenesis of depression disorders. Thus, it was shown that −511C/T polymorphism is associated with primary depression and post-stroke depression (PSD) at 2 weeks [29], with depression trajectory after acute coronary syndrome [34]. The −511C allele was also associated with more severe depression following chronic interpersonal stress exposure [30], and the T allele was associated with a positive history of major depression [55]. It was shown that depression in acute coronary syndrome was significantly associated with the level of IL-1β and −511T allele [34]. Another study reported that the −511T/T genotype was associated with both depression one week after surgery for breast cancer and persistent depression at one year of follow-up [38].
In a study by McQuaid et al. (2019) [32], it was shown that the severity of depressive symptoms was higher in individuals with the GG genotype of the IL1B rs16944 gene polymorphism. These results are consistent with earlier reports that carriers of the GG genotype have a greater severity of depressive symptoms [30]. The rs16944 IL1B was associated with childhood abuse as a predictor of depression scores. In particular, after childhood abuse, men carrying the rs16944*GG of IL1B showed particularly severe symptoms of depression [32]. In this way, the level of IL-1β and the −511C/T genotype, alone or together, may be biomarkers of depressive disorder. Targeted interventions for people with higher levels of IL-1β and the IL1B-511T allele may reduce the risk of depressive disorder [34].
IL1B rs1143643 was significantly associated with Mausdley Staging Method scores to determine treatment response in MDD [35]. In another study of depressive patients combined with childhood trauma, rs1143643 did not increase depressive symptoms. However, the minor A allele showed a protective effect against depressive symptoms after recent life stress [33]. Patients with GC and CC genotypes of rs1143623 (IL1B-1560G/ C) demonstrated different levels of disease severity as evaluated by the Hamilton Depression Rating Scale [18]. For the +3953C/T polymorphism of IL1B, no associations were found with depression in either the acute or chronic phases [34].
The results of the GWAS, published this year, suggest that specific SNPs, including rs2540315 and rs75746675 in the IL-1 receptor gene IL1R1, were associated with a rapid (within 240 min) antidepressant effect of ketamine infusion in patients with treatment-resistant depression [37]. An important limitation of the study is the small number of people examined (65 patients with treatment-resistant depression divided into 3 groups).
Interleukin-6 (IL-6) is a potent biomarker for depression, as its elevated plasma levels in patients with clinical depression have been confirmed by a range of studies [19,42,45]. Genetically-predicted IL-6 was associated with major depression in a multivariable mendelian randomization study (OR = 1.08; 95% C.I., 1.03–1.12) [56]. It has been shown that IL-6 levels are correlated with the IL6-634C/G polymorphism (rs1800796), and a G to C polymorphism at the −174 position of the IL6 promoter region appears to affect IL6 transcription [27,42]. The −572CC genotype and C allele were significantly associated with depression in the Han Chinese population [40].
It is also reported that the −174G/C polymorphism IL6 in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the Zung Self-rating Depression Scale [42]. Udina et al. (2013) found that carrying the CC genotype of rs1800795 IL6 is associated with less severe IFN-α-induced depression and anxiety [44]. Russian researchers report that −174G/C polymorphism was associated with depression comorbid to coronary heart disease. The frequency of the allele G in this group was higher compared with controls [41]. The polymorphic variant rs1800795 (IL6-174G/C) is associated with recent stress on current depressive symptoms and is associated with lifetime depression at a nominal significance level [41].
The polymorphic variant rs2228145 (Asp358Ala) of the IL-6 receptor gene (IL6R) was associated with a reduced risk of severe depression and/or psychosis; the adjusted 95% odds ratio for patients with the CC genotype compared with the AA genotype was 0.38 (CI 0.15–0.94). This same polymorphic variant was associated with elevated serum IL-6 levels (P = 5.5 × 10−22) [47].
Several studies suggest that IL-8 has neuroprotective functions [57]. At the same time, an investigation of IL8-251T/A in breast cancer patients found no association between the alleles and depression [38]. Furthermore, no association was found between IL8-251T/A and depression in a study of 732 elderly Koreans [58]. In the examination of a symptom in lung cancer, patients with IL8-251TT were more likely to experience severe depression but less susceptible to pain or fatigue [59].
Genetic studies of the anti-inflammatory cytokine IL-10 have shown that carrying genotypes GA and GG of rs1554286 IL10 is a predictor of anxiety (HR 1.85, p = 0.019) in early-stage breast cancer patients in China, which could help identify patients at high risk for psychological problems [60]. An investigation of 167 oncology patients showed that the rare AA genotype of rs1518111 was associated with subsyndromal depression [48].
A study of 398 breast cancer patients prior to surgery showed that the rs1295686*A of IL13 was associated with a symptom cluster of pain, fatigue, sleep disturbance, and depression [49].
IL-18 is expressed in the brain, and it is increased in patients with depression [50,61] and influences stress-related susceptibility to mood and anxiety symptoms by changing amygdala reactivity [62]. Reported that polymorphisms IL18-607A/C and IL18-137C/G were associated with the effects of antidepressant therapy [50]. Thus, patients carrying CA or AA genotypes of −607A/C and patients carrying GC or CC genotypes of −137C/G were significantly more prone to relapse after therapy and presented a significantly lower time to relapse [50]. Recent research on IL18 polymorphisms (rs187238, rs1946518 and rs1946519) has not found differences between depressive patients and healthy controls [61].
Meta-analysis data showed that the level of tumor necrosis factor-α (TNF-α) increased in MDD [63]. Increased levels of TNF-α may be conditioned by the presence of a range of specific polymorphic variants [64]. Higher TNF-α levels were associated with post-stroke depression at 2 weeks in the presence of the −850T allele [29]. Another study showed that the TNFA-857CT genotype was associated with increasing the risk for prenatal depression in a Mexican mestizo population, and the −238GA genotype reduced the risk [51]. Homozygous for the rare allele in rs1799964 TNFA belonged to the subsyndromal depressive symptoms in patients with breast cancer [52]. A GWAS showed that among 57 genes and 92 SNPs identified in MDD patients, only rs769178 TNFA was related to depression, and it remained significant after correcting for multiple testing [14].
A number of studies have reported that the TNFA-308G/A polymorphism (rs1800629) is associated with depression [31] and is a risk factor for suicide attempts in MDD [36]. It was found that the TT genotype and the T allele of rs1799964 (−1031T/C) were associated with low effectiveness of pharmacotherapy, and the CT genotype and C allele were associated with positive responses to the treatment of depressive disorder [18]. The opposite data of the metaanalysis showed that there was no association of the TNFA-308G/A alleles or genotypes with poststroke, late-life, maternal, or major depression [65]. Another recent study, including 83 Polish patients, found no statistically significant association between the genotype/allele frequency of TNFA-308G/A and TNFA-1031T/C and depression [64].
The AG genotype of the rs2166975 TGFA was associated with an increased risk of depression development, while the GG genotype of the rs2166975 TGFA reduced the risk. That genotype increased the risk of MDD only in the male population [53].
The TGFB + 869T/C polymorphism predicts low activity of TGF-β expression. The study in the Bulgarian population revealed a significant prevalence of the TT genotype of the +869T/C polymorphism in patients with depression (41.3%) compared with healthy subjects (21.2%) (p = 0.05, OR = 2.62). In addition, the combination of TT-GC genotypes (+869T/C, +915G/C) in the gene is negatively associated with disease recurrence of depression [54]. Genotype AA of rs1800469 TGFB was associated with an earlier age of depression onset, while GG genotype increased the severity of the depressive episode [53]. One study showed an association between the rare A allele of rs2229094 TNFA and subsyndromal depression [48].
Thus, literature data show that depression is associated with polymorphic variants of cytokines genes. These associations also include the severity of the depressive disorder or the response to therapy. This complements and expands the data on immune dysfunction in this disease. Further research is needed to determine the precise impact of these polymorphisms and to find potential predisposing or protective alleles that can be used as biomarkers for the risk of depression.

This entry is adapted from the peer-reviewed paper 10.3390/genes14071460

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