Associations between Tumor Necrosis Factor-α Polymorphisms and Risk of Psoriasis: A Meta-Analysis

Background

Tumor necrosis factor-α (TNF-α) may play an important role in the recalcitrant inflammatory and hyperproliferative dermatosis of psoriasis, and there may be a relationship between TNF-α polymorphisms and psoriasis risk.

Methods

We performed a meta-analysis to evaluate the associations between TNF-α polymorphisms and psoriasis. Electronic searches of Pubmed, Embase, and Web of Science were performed for all publications on the associations between TNF-α polymorphisms and psoriasis through September 26, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the associations.

Results

Sixteen case-control studies with a total of 2,253 psoriasis cases and 1,947 controls on TNF-α 308 G/A polymorphism and fourteen studies on TNF-α 238 G/A polymorphism with 2,104 cases and 1,838 controls were finally included into the meta-analysis. Overall, TNF-α 308 G/A polymorphism was significantly associated with decreased risk of psoriasis under three genetic comparison models (for A versus G: fixed-effects OR 0.71, 95%CI 0.62-0.82, P < 0.001; for AG versus GG: fixed-effects OR 0.67, 95%CI 0.57-0.78, P < 0.001; for AA/AG versus GG: fixed-effects OR 0.67, 95%CI 0.58-0.78, P < 0.001). In addition, TNF-α 238 G/A polymorphism was associated with increased risk of psoriasis under three genetic models (for A versus G: fixed-effects OR 2.46, 95%CI 2.04-2.96, P < 0.001; for AG versus GG: fixed-effects OR 2.69, 95%CI 2.20-3.28, P < 0.001; for AA/AG versus GG: fixed-effects OR 2.68, 95%CI 2.20-3.26, P < 0.001). Subgroup analysis by ethnicity identified a significant association between TNF-α 308 G/A polymorphism and decreased risk of psoriasis in both Caucasians and Asians and a significant association between TNF-α 238 G/A polymorphism and increased risk of psoriasis in Caucasians.

Conclusions

The meta-analysis suggests that TNF-α 308 G/A polymorphism is associated with decreased risk of psoriasis, while TNF-α 238 G/A is associated with increased risk of psoriasis.     

Association between TNF-α promoter G-308A and G-238A polymorphisms and obesity

Tumor necrosis factor-α (TNF-α), an adipokine, is produced in adipocytes, and the elevation of its levels has been linked to obesity and insulin resistance in some population. In this study the relationship between TNF-α promoter gene polymorphism and obesity in an Iranian population has been studied. Subjects were randomly selected from Tehran Cohort Lipid and Glucose Study. Adult participants placed in three groups according to their body mass index (BMI): BMI < 25, 25 ≤ BMI < 30, BMI ≥ 30 and under-18 subjects placed in two groups, under 85th percentile BMI and above 85th percentile. Finally, 244 persons were selected for G-308A and G-238A polymorphisms analysis. The FBS, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, cholesterol levels and blood pressure and HOMA of all subjects were measured. The polymorphism −308 and −238 were revealed by restriction fragment length polymorphism (RFLP; NCOI and MSPI) after the promoter site was amplified by PCR. The allele frequency of TNF-α polymorphism was in the Hardy–Weinberg equilibrium. There was no relation between BMI and the frequency of this allele. The fact that there is no association between G-308A and G-238A TNF-α promoter polymorphisms and obesity probably shows that it is not an important risk factor for obesity and consequently for cardiovascular disease.     

High Producer Haplotype (CAG) of -863C/A, -308G/A and -238G/A Polymorphisms in the Promoter Region of TNF-α Gene Associate with Enhanced Apoptosis of Lymphocytes in HIV-1 Subtype C Infected Individuals from North India

Introduction

The natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals. Host genetic factors may be one of the possible reasons for variable HIV-1 disease progression. Single nucleotide polymorphisms (SNPs) in the promoter region of TNF-α gene can influence its production. The aim of the present study was to determine the association of functional TNF-α SNPs and its associated parameters related to apoptosis that may influence the rate of HIV-1 disease progression.

Methods

Therapy naive, 100 HIV slow progressors (SPs), 100 HIV fast progressors (FPs), 50 HIV exposed but seronegative individuals (ESNs) and 260 healthy controls from same ethnic origin were recruited. Genotyping of TNF-α variants (−863C/A, -308G/A and -238G/A) was done using PCR-RFLP. CD4 counts were determined by flow cytometry. Plasma viral load was estimated by COBAS AMPLICOR HIV-1 monitor test. Plasma TNF-α concentration was estimated by Human CBA Th1/Th2 cytokine kit. The lymphocyte mitochondrial membrane potential was measured by JC-1 dye by flow cytometry.

Results

Genotype and allele frequency of TNF-α -238G/A and -863C/A was not significantly different in HIV-1-infected patients when compared to controls, while that of TNF-α -308G/A variant (high TNF-α producer) was significantly higher in FPs compared to SPs (p<0.01, OR = 3.43). Haplotype analyses also showed that carriers of high TNF-α producing haplotype CAG was significantly more common among FPs compared to SPs (p<0.01, OR = 3). The circulating TNF-α levels in blood also correlated well with genotypes. The lymphocyte mitochondrial membrane potential of FPs having CAG haplotype was significantly low as compared to wild type (CGG) haplotype (417±22 vs 571±28, p<0.01).

Conclusion

High producer haplotype, CAG of TNF-α gene associates with enhanced apoptosis of lymphocytes in HIV-1 infected individuals, hence faster progression to AIDS. However, further functional studies are needed to confirm this association and this knowledge may help clinicians to better understand the disease outcome.     

Associations between TNF-α Polymorphisms and Pneumonia: A Meta-Analysis

Background

Several studies evaluated the associations of tumor necrosis factor-α (TNF-α) polymorphisms with pneumonia in different populations. However, the results were conflicting and controversial.

Methods

Databases including PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Data were extracted independently by two investigators. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated.

Results

Twelve case-control studies and one cohort study were included. Overall, no association between TNF-α −308A/G polymorphism and pneumonia risk was observed for AA +AG vs. GG (OR = 1.13; 95% CI 0.99–1.30; P = 0.07). In addition, TNF-α −308A/G polymorphism was not associated with pneumonia mortality (OR = 1.96; 95% CI 0.94–4.09; P = 0.07). Furthermore, there was no association of TNF-α −238A/G polymorphism with the risk of pneumonia (OR = 1.38; 95% CI 0.84–2.28; P = 0.20).

Conclusions

TNF-α −308A/G, −238A/G polymorphisms were not associated with pneumonia risk. Moreover, TNF-α −308A/G polymorphism did not play a role in the pneumonia mortality risk.     

Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients

Objective

Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients.

Patients and Methods

Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied.

Results

Evolution time of the infection was 21 years in both patients’ groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis.

Conclusion

It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections.     

Association of TNF-α polymorphisms (−857, −863 and −1031), TNF-α serum level and lipid profile with acne vulgaris

BackgroundAcne is an inflammatory condition principally affected by genetic and dietary factors. Investigation into functional polymorphisms of TNF-α gene and their association with acne vulgaris will be helpful in exploring genetic influence on skin immune mediated inflammatory events. In the present study, we analyzed association of TNF-α gene polymorphisms, its expression levels and lipid profiles in a large cohort of acne patients and controls.MethodsWe used PCR-RFLP to study association of TNF-α polymorphisms at −857C/T, −863C/A and −1031 T/C sites with acne vulgaris. Lipid profiles were measured using enzymatic end-point method. The serum levels of TNF-α and apolipoprotein a were measured using ELISA. NIH, LDlink was used to investigate patterns of linkage disequilibrium across south Asian reference genome (Punjabi from Lahore Pakistan).ResultsWe found that TNF-α −863 polymorphism is strongly associated with acne in overall population as well as in gender and severity based groups of acne patients. Polymorphisms at −863 and −1031 position were in linkage disequilibrium. Importantly, TNF-α serum level was significantly increased in acne patients with severe disease symptoms. Furthermore, levels of total cholesterol (TC) and triglycerides (TG) were significantly increased, whereas high density lipoprotein cholesterol (HDL-C) level was significantly decreased in acne patients. The levels of apolipoprotein a varied widely in studied populations and no significant difference was found in the analyzed groups.ConclusionIn conclusion, we found that TNF-α expression increases in acne patients affected by TNF-α polymorphisms, and that the lipid profile is specifically disrupted in acne patients.     

Macrophage responses to interferon-γ are dependent on cystatin C levels

The aim of the present investigation was to elucidate possible effects of cystatin C on inflammatory responses mediated by macrophages. Previously it has been shown that in vitro treatment of murine peritoneal macrophages with interferon-γ (IFN-γ) causes a down-regulation of cystatin C secretion. To investigate whether such changes in cystatin C expression in turn can affect inflammatory responses mediated by macrophages, we have compared effects of IFN-γ on macrophages isolated from wild-type (cysC^+/+) and cystatin C knockout (cysC^−/−) mice. It was shown that IFN-γ-primed cysC^−/− macrophages exhibit significantly higher interleukin-10 (IL-10) but lower tumor necrosis factor-α (TNF-α) expression, and reduced nuclear factor (NF)-κB p65 activation, compared to similarly primed cysC^+/+ cells. Exogenously added cystatin C enhanced IFN-γ-induced activation of NF-κB p65 and increased mRNA levels for inducible NO synthase (iNOS) in cysC^−/− macrophages as well as levels of nitric oxide and TNF-α in the cell culture medium, in agreement with an enhanced pro-inflammatory response. Accordingly, IFN-γ-induced IL-10 mRNA expression in cysC^−/− macrophages was down-regulated by exogenously added cystatin C. Taken together, our data provide evidence that changes in cystatin C levels alter macrophage responses to IFN-γ. The latter down-regulates the production of cystatin C, which leads to a suppressed inflammatory condition with enhanced IL-10 levels and down-regulated TNF-α and NF-κB. It is concluded that cystatin C through this effect can act as an immunomodulatory molecule.     

IMPLICATION OF TNF-α CONVERTASE (TACE/ADAM17) IN INDUCIBLE NITRIC OXIDE SYNTHASE EXPRESSION AND INFLAMMATION IN AN EXPERIMENTAL MODEL OF COLITIS

Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-α convertase (TACE; ADAM17). TNF-α plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-α levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-α and NO−x levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-α. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-α release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-α release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD.