肿瘤坏死因子α启动子基因多态性与胸腺瘤的相关性

目的研究肿瘤坏死因子(TNF)-α启动子基因多态性与胸腺瘤发病的相关性。方法采用聚合酶链反应加基因测序技术对126例胸腺瘤患者与245名健康对照者TNF-α启动子区进行基因分型,比较TNF-α-863、-308、-238、-806以及-857 5个位点等位基因出现频率的差异。结果胸腺瘤患者TNF-α基因-857位点T等位基因和CT+TT基因型显著高于健康对照组(分别为χ2=6.449,P=0.011;χ2=4.874,P=0.027),而TNF-α-863、-308、-238、-806等位点的等位基因频率与健康对照组比较差异无统计学意义。结论 TNF-α基因-857位点T等位基因与胸腺瘤相关,且其可能为胸腺瘤患者一个新的易感基因标记。     

Increased plasma level of tumor necrosis factor α in patients with narcolepsy in Taiwan

BackgroundNarcolepsy is a neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and abnormal rapid eye movement (REM) sleep. Tumor necrosis factor α (TNF α) and its cognate receptors have been reported to be involved in the pathophysiology of narcolepsy in addition to the HLA antigen system. Our study aimed to determine if the TNF-α system was associated with narcolepsy in our patients.MethodsWe first measured the plasma level of TNF α in 56 narcoleptic patients and 53 control subjects using a highly sensitive enzyme-linked immunosorbent assay. We next determined the genotype of three single nucleotide polymorphisms (SNPs) (T-1031C, C-863A, and C-857T) at the promoter region of the TNF-α gene and one missense SNP (T587G, M196R) at the exon 6 of the tumor necrosis factor receptor 2 gene, TNFR2, in a sample of 75 narcoleptic patients and 201 control subjects by direct sequencing analysis.ResultsWe found a significant elevation of plasma level of TNF α in patients with narcolepsy compared with the control subjects (4.64 pg/mL vs 1.06 pg/mL; P = .0013). However, we did not find significant differences between these two groups in the allelic and genotypic distributions of the investigated polymorphisms.ConclusionsOur study suggests that an increased TNF-α level was associated with narcolepsy in our patients, and that chronic inflammation due to various factors might have led to the increased TNF-α levels found in our patients.     

肿瘤坏死因子基因与精神分裂症的传递不平衡研究

目的 探讨肿瘤坏死因子-α(TNF-α)基因和肿瘤坏死因子-β(TNF-β)基因与精神分裂症的关系.方法 收集172个广东潮汕地区的精神分裂症核心家系,将172例精神分裂症患者分为偏执型(96例)和非偏执型(76例),用聚合酶链反应-限制性片段长度多态性方法 ,检测所有研究对象的TNF-α的3个多态性位点(-C863A、-G308A、-G238A)和TNF-β+A252G位点的等位基因频率和基因型频率,并进行传递不平衡检验(TDT).结果 (1)单位点TDT检验,TNF-β+A252G位点杂合子父母过多地传递等位基因G给患者(X2=5.49,Pc＜0.05),而TNF-α的3个多态性位点(-C863A、-G308A、-G238A)均未发现传递不平衡.(2)多位点联合进行单体型分析,未显示在精神分裂症核心家系中存在传递不平衡;但在96个偏执型精神分裂症核心家系中,有一种常见单体型[(-863C,-308G,-238G,+252G);X2=7.20,Pc＜0.05]存在偏向传递.结论 在广东潮汕人群中,TNF-α和TNF-β基因与精神分裂症可能存在某些关联,该基因可能是偏执型精神分裂症的易感基因.     

Arterial stiffness and endothelial function in obstructive sleep apnoea/hypopnoea syndrome

BackgroundObstructive sleep apnoea–hypopnoea syndrome (OSAHS) is associated with increased cardiovascular morbidity and mortality. Our study examined arterial stiffness and endothelial function in subjects with OSAHS with no known cardiovascular disease compared to well-matched controls.MethodsTwenty subjects with OSAHS (defined as apnoea–hypopnoea index [AHI] ⩾15 and Epworth Sleepiness Scale score ⩾11) without cardiovascular disease and 20 well-matched controls underwent a comprehensive evaluation of arterial stiffness and endothelial function. Arterial stiffness was measured by applanation tonometry and cardiovascular magnetic resonance imaging (MRI) and endothelial function assessed by measuring vascular reactivity after administration of glyceryl trinitrate and salbutamol.ResultsSubjects with OSAHS had increased arterial stiffness (augmentation index 19.3 [10.9] vs. 12.6 (10.2)%; p = 0.017) and impaired endothelial function (change in augmentation index following salbutamol −4.3 (3.2) vs. −8.0 (4.9)%; p = 0.02) compared to controls. Aortic distensibility, a measure of arterial stiffness, was negatively correlated with the AHI.ConclusionsOur findings suggest that even in the absence of known cardiovascular disease, subjects with OSAHS have increased arterial stiffness and impaired endothelial function and are at increased risk for cardiovascular disease.     

When grief makes you sick: Bereavement induced systemic inflammation is a question of genotype

Although bereavement is associated with increased morbidity and mortality in the surviving spouse, some widow(er)s remain healthy. Genetic variability in expression of inflammatory markers in response to stress may be the key to this observation. The present study compares bereaved vs. married/partnered older adults, investigating the impact of bereavement status, pro-inflammatory cytokine single nucleotide polymorphisms (SNPs) on circulating markers of inflammation and hypothesizing a gene by environment (GxE) effect. The study sample included 64 older adults, of which 36 were widow(er)s. Circulating levels of inflammatory markers IL-6, IL-1RA and sTNFRII were measured. Participants were genotyped for SNPs in the IL-6 gene (IL-6 -174 and -572), the IL-1β gene (IL-1β -511), and TNF-α gene (TNF-α -308). Grief severity was assessed with the Inventory of Complicated Grief. Bereaved participants had higher circulating levels of IL-1RA and IL-6. This increase could not be explained by pro-inflammatory genotype frequency differences, or Complicated Grief diagnosis. However, a GxE effect with the IL-6 -174 SNP moderated individual vulnerability to higher circulating levels of inflammation resulting from bereavement exposure. These results suggest a possible mechanism for the increase in morbidity and mortality in the surviving spouse. Genetic variability interacts with an environmental stressor, leading to increased inflammatory markers in genetically susceptible subjects only. For these patients, clinical interventions for bereavement-related stressor reduction might be crucial for overall health.     

Role of IL-10 −1082, IFN-γ +874, and TNF-α −308 Genes Polymorphisms in Suicidal Behavior

In this study, it was determined whether the IL-10 ?1082, IFN-γ +874, and TNF-α ?308 polymorphisms were associated with suicidal behavior. One hundred forty five patients with suicidal behavior and 160 normal individuals were genotyped for IL-10 ?1082, IFN-γ +874, and TNF-α ?308 polymorphisms using ASO-PCR method. TNF-α ?308 G/G genotype has been increased in males with completed suicide behavior versus control group (p value = 0.017). IL-10 ?1082 A/A genotype is higher in both male and female suicide completed groups (p value = 0.017). IFN-γ (+874) A/A genotype was significantly higher in males with completed suicide behavior versus normal male control (p value = 0.027). It can be concluded that IL-10, IFN-γ, and TNF-α polymorphisms may play a role in suicidal behavior.     

A custom-made mandibular repositioning device for obstructive sleep apnoea–hypopnoea syndrome: the ORCADES study

BackgroundMandibular repositioning devices (MRDs) are usually recommended as the first therapy option in patients with mild-to-moderate obstructive sleep apnoea (OSA). However, data on the long-term efficacy of MRDs are limited, not only in OSA patients who are noncompliant with continuous positive airway pressure (CPAP) but also in those with more severe OSA. The ORCADES study aimed to prospectively determine the long-term efficacy and tolerability of two custom-made Narval^™ MRDs for obstructive sleep apnoea–hypopnoea syndrome (OSAHS) patients. The interim 3- to 6-month data are reported.MethodsEligible patients had OSAHS and had refused or were noncompliant with prescribed CPAP. Outcome measurements after gradual mandibular advancement titration included: apnoea–hypopnoea index (AHI), oxygen saturation, sleepiness, symptoms, quality of life, side effects and compliance.ResultsA total of 369 patients were included. Overall, MRD treatment was successful (≥50% decrease in AHI) in 76.2% of the participants; complete response (AHI <10/h) was achieved in 63.5%. Severe OSAHS was effectively treated (AHI <15/h) in about 60% of the participants; 38% had complete symptom resolution. Mandibular repositioning devices significantly decreased subjective sleepiness, eliminated symptoms and improved quality of life. They were well tolerated and compliance was excellent. Only 8% of the participants stopped MRD treatment due to side effects.ConclusionCustom-made Narval^™ MRDs are effective for mild to severe OSA in patients who refuse or are noncompliant with CPAP. They are well tolerated and have excellent compliance.     

No association between the tumor necrosis factor-alpha gene promoter polymorphisms and schizophrenia in a Japanese population

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotrophic cytokine and exerts neuroprotective and neurodegenerative effects in brain. Several studies have indicated that TNF-alpha is likely related to the pathogenesis of schizophrenia. Recent genetic investigations have revealed that a TNF-alpha gene promoter polymorphism (-G308A) is associated with schizophrenia, although negative findings have also been reported. To assess whether the TNF-alpha gene promoter variants including -G308A could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (265 cases and 424 controls) and the transmission disequilibrium test (TDT) analysis (83 trios) for four polymorphisms (-G238A, -G308A, -C857T and -T1031C) in Japanese subjects. In a case-control analysis, there was no significant association between the promoter polymorphisms or haplotypes in the TNF-alpha gene and schizophrenia. In the TDT analysis, we also did not observe transmission distortion. Our results suggest that the above four polymorphisms in the promoter region of the TNF-alpha gene appear not to confer increased susceptibility for schizophrenia in a Japanese population.     

Tumor necrosis factor-alpha gene promoter polymorphisms in chronic schizophrenia.

BACKGROUND: Alterations in cytokine levels in patients with schizophrenia have been documented. Polymorphisms in these cytokine genes are thus potential genetic markers for schizophrenia. The aim of this study was to investigate four biallelic polymorphisms in the tumor necrosis factor-alpha (TNFalpha) gene promoter in relation to susceptibility to schizophrenia. METHODS: Three hundred two patients and 152 control subjects were genotyped and frequencies of genotypes and alleles were compared for the -1031T/C, -863C/A, -857C/T, and -308G/A polymorphisms. Genotype and allele frequencies were compared between controls and patients. RESULTS: There were statistically significant differences in genotype distribution and allele frequencies for the -308 polymorphism (p <.001). Genotype distribution and allele frequencies of the other three polymorphisms were not different between patients and reference controls. CONCLUSIONS:The -308 polymorphism or another genetic variant in linkage disequilibrium with it could be a susceptibility factor for chronic schizophrenia.     

Migraine and tumour necrosis factor gene polymorphism

To assess the possibility of an association between TNF gene polymorphisms and migraine without aura, a case-control study was performed in a Sardinian sample. Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development. Several studies suggest that tumour necrosis factors (TNF) (TNF-α and lymphotoxin-alpha or TNF-ß) may be involved in the pathophysiology of migraine. The TNF-α and TNF-ß genes are located on chromosome 6p21.3 in the human leukocyte antigene (HLA) class III region. We evaluated 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls. The polymorphisms G308A of the TNF- α gene, and G252A of TNF-β gene were determined by NcoI restriction fragment length polymorphism analysis. We found a statistically significant difference in allele (p = 0.018; OR = 1.46 95 % CI: 1.066 to 2.023) and genotype (trend χ2 = 5.46, df = 1, p = 0.019) frequencies of TNF-β gene, between cases and controls. Allele and genotype frequencies of TNF-α polymorphism did not differ significantly between the two groups. These data suggest that subjects with the TNFB2 allele have a low risk of developing migraine without aura and/or that the polymorphism of the TNF-β gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.     

Suicide attempt in mental disorders (MeDi): Association with 5-HTT,IL-10 and TNF-alpha polymorphisms

BackgroundMental disorders (MeDi) and suicide attempts (SA) are influenced by environmental and genetic factors. Genetic polymorphism studies have identified some candidate genes for suicidal behaviour in people with MeDi.ObjectiveTo evaluate MeDi and SA in relation to the presence of rs2020933 (5-HTT), rs1800871 (IL-10) and rs1800629 (TNF-α) polymorphisms.MethodsA questionnaire for identification and general data, a brief quality of life assessment (WHOQOL-brief), the scale of suicide ideation by Beck and the MINI International Neuropsychiatric Interview were used in this study. DNA was obtained using buccal mucosa swab samples, and genotyping was performed using real-time polymerase chain reaction. A total of 306 patients were assessed with MeDi; 161 patients had MeDi and a history of SA, and 145 patients had MeDi and no history of SA. The study had 175 subjects in the control group.ResultsThe TNF-α rs1800629 -308A/G genotype was significantly associated with function as a protection factor in the control group compared with MeDi without SA. The TNF-α rs1800629 -308G allele appeared as risk factor for MeDi compared to the control group, for female gender. Additionally, the −308A/G + A/A genotype appeared as protection factor for the control group compared to the group with MeDi. For TNF-α, the −308G allele appeared as risk factor for the number of SA (1 time) compared to the control group.ConclusionThe IL-10 (rs1800871) and 5-HTT (rs2020933) SNPs were considered to have inadequate statistical power. The rs1800629 (TNF-α) polymorphism may be associated with MeDi without SA, MeDi in females and the number of SA (1 time) in the studied group.     

Epilepsy and pro-inflammatory cytokines. Immunomodulating properties of antiepileptic drugs

Epilepsy is a complex and multifactorial phenomenon. Accumulating evidence suggests that the immune system may play an important role in neuronal excitability and epileptogenesis. In many animal models of epilepsy, seizures induced chemically or electrically cause glial activation and increased expression of pro-inflammatory cytokines (IL-1 β, TNF- α, IL-6). The studies show that the IL-1 β /IL-1Ra system may modulate epileptic activity and contribute to neuronal excitability. Exogenous IL-1 β has pro-convulsive properties. The action of TNF- α and IL-6 is complex (either stimulating or inhibitory action of these cytokines on seizures, depending on their concentration and the type of receptors involved in the response). In vitro and in vivo experiments show that antiepileptic drugs could affect cytokine levels (e.g. valproate significantly inhibited production of TNF- α and IL-6 by human monocytic leukaemia cells). In epilepsy patients studies (including ex vivo) show elevated levels of IL-1 β, IL-2, IL-5, IL-6 or TNF- α after carbamazepine, valproic acid and phenytoin. This review surveys the current state of knowledge regarding effects of pro-inflammatory cytokines on seizure pathogenesis. Cytokine modulatory actions of some antiepileptic drugs are also discussed.     

Peripheral levels of C-reactive protein,tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability

ImportanceIt is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.ObjectiveTo run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.Data sourcesSystematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.Study selectionCase-control studies reporting inflammatory mediators' levels in BD and controls.Data extraction and synthesisSummary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g).Main outcomes and measuresCo-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.ResultsOut of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31–1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46–1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19–0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI −0.68–0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.Conclusions and relevancePeripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.     

Interaction analysis between 5-HTTLPR and TNFA −238/−308 polymorphisms in schizophrenia

Summary. This study investigated the potential interaction between the polymorphisms of serotonin transporter gene (SLC6A4, a 44 base pair insertion/deletion in the promoter region, 5-HTTLPR) and tumor necrosis factor-α gene (TNFA; −238G/A and −308G/A polymorphisms) on the development of schizophrenia, as well as the interaction of the three polymorphisms in relation to symptomatology, family history, onset age and antipsychotic treatment response. Genomic DNA analyses with polymerase chain reaction (PCR) was used for the genotyping. One hundred and fifty-two (152) patients with schizophrenia and 152 normal controls participated in the study. Any associations between the individual polymorphism and schizophrenia were not found. However, marginal association between subjects with both TNFA −238 A allele (genotype AA plus AG) and 5-HTTLPR s allele (ss plus sl) and presence of family history was found (p = 0.023; p = 0.026). The subjects with TNFA −308 AG genotype showed higher change in PANSS total score (p = 0.028). No significant interaction effect between 5-HTTLPR and TNFA −238/−308 polymorphisms either on the development of schizophrenia or on antipsychotics treatment response and psychopathology was found, although a significant interaction effect for subjects carrying TNFA −238 AG and −308 AA genotypes on a positive family history was observed (p = 0.017). These results suggest that the interaction effects between 5-HTTLPR and TNFA −238/−308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and is not associated with clinical variables, antipsychotic treatment response and psychopathological features, except for family history of disease, at least in the Korean population.     

Association between tumor necrosis factor-alpha promoter polymorphism and Alzheimer's disease

Tumor necrosis factor-alpha (TNFalpha) gene polymorphisms have been reported to be associated with Alzheimer's disease (AD) in Caucasian populations. Three TNFalpha polymorphisms (-857, -863, and -1,031) were studied in a Chinese population. A high-risk TNFalpha haplotype (-1,031C-863C-857C) with an odds ratio of 2.54 (95% CI 1.37 to 4.79) for AD was identified. No interaction effect of APOE and TNFalpha genotypes was found, but both acted as important risk factors for AD.     

Pro-inflammatory cytokines are associated with the development of post-stroke depression in the acute stage of stroke: A meta-analysis

ABSTRACT

Background: Pro-inflammatory cytokines may be associated with post-stroke depression (PSD); however, results from different studies are inconsistent.

Objectives: To investigate whether pro-inflammatory cytokines are associated with the development of PSD in acute stroke.

Methods: PubMed, Embase, and Web of science were searched for relevant literature. Meta-analyzes were performed to determine whether the baseline blood concentrations of pro-inflammatory cytokines differed between acute stroke patients with and without depression. Sensitivity analyzes and regression analyzes were conducted to explore sources of heterogeneity.

Results: We included 889 acute stroke patients from eight original studies, 312 of whom developed PSD and 577 did not. The serum concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were higher in the PSD group, compared with the non-PSD group (IL-6: SMD = 1.26, 95% CI = [0.55, 1.97], P < 0.001; TNF-α: SMD = 0.61, 95% CI = [0.13, 1.10], P = 0.010).

Conclusions: This study indicates IL-6 and TNF-α as potential biomarkers of PSD in the acute stage of stroke and provides theoretical support for the early prevention and treatment of PSD.     

TNF-alpha polymorphisms in multiple sclerosis: no association with -238 and -308 promoter alleles, but the microsatellite allele a11 is associated with the disease in French patients

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is believed to play an important role in multiple sclerosis (MS) pathogenesis. The objective of this study was to determine whether sequence variation in the TNF-alpha gene is associated with MS. Bi-allelic polymorphisms in the TNF-alpha promoter region (TNF-alpha -238 and -308) and microsatellite TNF-alpha were previously reported. We investigated these polymorphisms in 74 French patients with MS, compared with 75 controls. No significant differences regarding the TNF-alpha -238 and -308 polymorphisms were observed between MS patients and controls. Allele frequency for the a11 allele is in very significant association (P<0.0001) with MS, due in part to the association of the a11 allele with the HLA-DRB1*15 allele in patients.     

Association between TNF-α promoter -308A/G polymorphism and tardive dyskinesiain Chinese Han patients with schizophrenia

Objective

Previous studies have indicated that the immune may be involved in the pathogenesis of tardive dyskinesia (TD). Some genetic polymorphisms in the human leukocyte antigen (HLA) I and II regions have been associated with TD, and the tumor necrosis factor-α (TNF-α) gene is located in the HLA III region. TNF-α levels in the striatum significantly increased in haloperidol-induced TD in rats. The TNF-α gene −308A/G single nucleotide polymorphism (SNP) has been shown to directly influence TNF-α expression. The genetic association between the TNF-α gene −308A/G SNP and TD is unclear. The present study investigated whether this variation is associated with clinical phenotypes and TD in schizophrenia in a genetically homogeneous northern Chinese Han population.

Methods

We genotyped the TNF-α gene −308A/G SNP in patients with schizophrenia with TD (n = 350) and without TD (n = 410). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of TD and psychopathology of schizophrenia, respectively.

Results

The allele and genotype frequencies did not significantly differ between patients with schizophrenia with and without TD (p > 0.05). No significant difference was found in the total AIMS score between the genotypes (p > 0.05). However, the PANSS negative symptom subscore was associated with risk for TD (p = 0.004), and a significant difference was found in total AIMS score between the genotypes in TD patients (p = 0.013).

Conclusion

The TNF-α gene −308A/G polymorphism does not appear to play a major role in the susceptibility to TD in patients with schizophrenia in a northern Chinese Han population. However this polymorphism may play a role in the TD severity.