Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis

A great number of association studies have been performed to identify the genes involved in the etiology and prognosis of sarcoidosis. We performed a systematic review of case-control studies through the PubMed database and evaluated them for a possible inclusion into a meta-analysis in order to assess whether the reported genetic polymorphisms are the risk factors of sarcoidosis. Case-control studies with clear diagnostic criteria and interventions were included. Only investigations of a single polymorphism/gene involvement in sarcoidosis reported more than five times were selected. Aggregating data from 12 studies on ID/ACE polymorphisms, the odds ratio (OR) for sarcoidosis, if the polymorphism was considered under the dominant genetic model, was not significantly increased: 1.19 (95% CI 0.98–1.43); OR under the recessive model was 1.20 (95% CI 0.98–1.46). In seven case-control studies on −308/TNF-α polymorphism, the OR for sarcoidosis if the polymorphism considered under the dominant genetic model was significantly increased at 1.47 (95% CI 1.03–2.08); the OR under the recessive model was 1.39 (95% CI 0.67–2.90). In conclusion, the results showed that the TNF-α genotype could be a significant risk factor for sarcoidosis, whereas the risk of sarcoidosis due to the ACE genotype was not substantially elevated.     

Effect of IL-1β and TNF-α polymorphisms on the prognosis and survival of gastric cancer patients

So far, a number of association studies have focused on the effect of polymorphisms in IL-1β and TNF-α genes on the susceptibility to gastric cancer (GC). Here, we evaluate the possible association between common polymorphisms in the IL-1β and TNF-α genes with various clinicopathological characteristics, including overall survival of GC patients. Restriction fragment length polymorphism analysis was performed for IL-1β-31(T?>?C) and IL-1β-511(C?>?T) and TNF-α-857 (C?>?T) polymorphisms in 130 GC patients. IL-1β-31CC and IL-1β-511TT genotypes held a significantly lower risk of lymphatic invasion (IL-1β-31CC vs. others: adjusted OR?=?0.39, 95% CI?=?0.15-0.96, P?=?0.04, IL-1β-511TT vs. others: adjusted OR?=?0.23, 95% CI?=?0.08-0.67, P?=?0.007). The IL-1β-31CC and IL-1β-511TT genotypes were weakly associated with reduced risk of venous invasion (IL-1β-31CC vs. others: adjusted OR?=?0.35, 95% CI?=?0.12-1.05, P?=?0.06, IL-1β-511TT vs. others: adjusted OR?=?0.32, 95% CI?=?0.08-1.20, P?=?0.09). The IL-1β-511TT genotype was also weakly associated with reduced risk of lymph node metastasis (IL-1β-511TT vs. others: adjusted OR?=?0.42, 95% CI?=?0.17-1.04, P?=?0.06). When the TNF-α-857CT and TNF-α-857-TT genotypes were considered as T carrier, the patients with TNF-α-857T carrier showed significantly better overall survival than patients with CC genotype (P?=?0.011). GC patients who have both IL-1β-31 CC and IL-1β-511 TT genotypes and have at least one of protective genotypes (IL-1β-31 CC, IL-1β-511 TT, TNF-α-857 T carrier) were also associated with better prognostic factors, such as lymphatic and venous invasion better survival. IL-1β-31CC, IL-1β-511TT genotype, and TNF-α-857T carrier may have protective effect against GC progression.     

TNF-α promoter single nucleotide polymorphisms and haplotypes associate with susceptibility of immune thrombocytopenia in Chinese adults

Objective

Tumor necrosis factor-alpha (TNF-α) participates as a candidate susceptibility factor for immune thrombocytopenia (ITP). This study attempted to investigate the association between five single nucleotide polymorphisms (SNPs) spanning the TNF-α promoter and the susceptibility of primary ITP in Chinese Han adults.

Methods

In 215 adult primary ITP patients and 206 healthy controls, SNPs were detected by PCR-RFLP and PCR-SSP. The χ² test or fisher’s exact test was used to compare frequencies of genotypes and alleles between patients and controls. Haplotypes were analyzed with the SHEsis online program. TNF-α, IFN-γ and Galectin-9 mRNA of 35 newly diagnosed adult ITP patients and 35 healthy controls were detected by qRT-PCR.

Results

The haplotype GGC (−238G/−308G/−857C) of TNF-α promoter was significantly associated with a decreased susceptibility of primary ITP, especially in males. The relative levels of mRNA expression of TNF-α, IFN-γ and Gal-9 in adult active primary ITP patients was significantly up-regulated compared with patients in remission and controls.

Conclusions

This study represented the first report that the haplotype GGC of TNF-α was differentially associated with the susceptibility of primary ITP in Chinese Han adults. The up-regulation of TNF-α, IFN-γ and Galectin-9 was significantly correlated with active primary ITP in adult patients.     

Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

The tumor necrosis factor-α (TNF-α) promoter ? 238A/G polymorphism has been repeatedly associated with systemic lupus erythematosus (SLE), but findings are not consistent across studies. Our aim was to do a meta-analysis to assess the association between TNF-α promoter ? 238A/G polymorphism and SLE. Eleven published studies of this polymorphism with SLE in different ethnic groups were identified using a Medline search. Meta-analysis was performed for genotypes AA versus GG, GA versus GG, AA versus GG+GA, GA+AA versus GG, and A allele versus G allele in a fixed/random effect model. The overall odds ratio (OR) of the AA versus GG+GA genotypes was 3.46 (95% CI = 1.35–8.83, P = 0.01), and a similar result was found in Caucasian population (OR = 4.62, 95% CI = 1.20–17.80, P = 0.03); the overall OR of the AA versus GG genotypes was 3.36 (95% CI = 1.32–8.55, P = 0.01), and a similar result was found in Caucasian population (OR = 4.29, 95% CI = 1.11–16.53, P = 0.03); the OR of the GA versus GG genotypes was 0.48 (95% CI = 0.30–0.75, P = 0.001) in Caucasian population. In conclusion, this meta-analysis demonstrates the association between TNF-α promoter ? 238A/G polymorphism and SLE, especially in Caucasian population.     

CXCL12 rs266085 and TNF-α rs1799724 polymorphisms and susceptibility to cervical cancer in a Chinese population

Further research is required to identify single nucleotide polymorphisms (SNPs) associated with cervical cancer. The aim of this study was to assess the association of TNF-α/rs1799724 and CXCL12/rs266085 polymorphisms with susceptibility to cervical cancer in Han Chinese population in Shandong Province. 348 patients with cervical squamous cell carcinoma, including CIS (121) and invasive carcinoma (227), and 351 healthy controls. Genomic DNA was isolated from peripheral blood and genotyping for TNF-α/rs1799724 and CXCL12/rs266085 was carried out using TaqMan SNP Genotyping Assays. TNF-α/rs1799724 polymorphism showed the C-allele was less prevalent among cases as compared to controls (74.3% vs. 92.0%), while the T-allele was more prevalent among cases (P=0.000, OR=3.99, 95% C.I.: 2.90-5.51). CXCL12/rs266085 polymorphism showed the C-allele was less prevalent among cases as compared to controls (41.2% vs. 49.7%), while the T-allele was more prevalent among cases (P=0.001, OR=1.41, 95% C.I.: 1.14-1.74). The genotype and allele frequencies of these two SNPs did not differ between CIS and invasive squamous cell carcinoma (P>0.05). Moreover, the allele frequencies of rs1799724 were significantly different between controls without or with HPV infection (P<0.05). Neither the genotype nor allele frequencies of rs266085 were statistically different between HPV-negative and positive controls. TNF-α/rs1799724 and CXCL12/rs266085 polymorphisms are associated with cervical cancer. C->T polymorphism of these two SNPs and HPV infection are linked to high risk for cervical cancer.     

Evaluation of TLR9 expression on PBMCs and CpG ODN-TLR9 ligation on IFN-α production in SLE patients

Context: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoreactive antibodies. Recent findings revealed the importance of innate immune responses, especially Toll-like receptors (TLRs) in the pathogenesis of SLE.

Objective: In this study, the level of TLR9 expression on peripheral blood mononuclear cells (PBMCs) was analyzed. The levels of produced IFN-α were also measured in supernatant of PBMCs from SLE patients and healthy controls after stimulation with CpG ODN2216 which is a plasmocytoid dendritic cell (pDC)-specific TLR9 ligand.

Materials and methods: TLR9 expression was analyzed by real-time polymerase chain reaction (PCR) and flow cytometry in 35 SLE patients and 38 healthy controls and IFN-α concentration was measured in supernatants using enzyme-linked immunosorbent assay (ELISA).

Results: The results showed that the TLR9 expression in the mRNA and the protein level was significantly higher in PBMCs from SLE patients. However, IFN-α concentration in patients and controls significantly increased in response to CpG stimulation but this increase was significantly higher in healthy controls compared with SLE patients. Our results do not show any association between taking hydroxychloroquine and reduction in IFN-α production in SLE patients.

Discussion and conclusions: Regarding the findings of the study, there is the possibility that TLR9 has played a role in SLE pathogenesis, and consequently it implies that TLRs can be considered to be the therapeutic targets for systemic autoimmunity. We may conclude that PBMCs in patients are functionally impaired in response to TLR ligation via innate response stimulating pathogen-associated molecular patterns (PAMPs).     

Possible effect of gene polymorphisms on the release of TNFα and IL1 cytokines in coal workers’ pneumoconiosis

It has been shown that coal dust exposure stimulates inflammatory response leading to increased release of cytokines from monocytes such as TNF-alpha and IL1. These released cytokines play the key role in the pathogenesis of pneumoconiosis including coal workers’ pneumoconiosis. In this study, we investigated TNFA, IL1A, IL1B and IL1RA genes variations on basal, lipopolysaccharide and coal dust-induced cytokine release from blood monocytes of homozygous allele and minor variant allele carriers in Turkish coal workers and CWP patients. According to the genotyping results, TNFA –238 gene polymorphism was found as a risk factor in CWP development (OR=3.79) and to in vitro results; release of both TNF-alpha and IL1 cytokines from the monocytes in CWP patients was significantly increased compared to the healthy workers. Also, LPS and coal dust stimulated release of TNF-alpha, which was significantly higher in allele 2 carriers compared to subjects carrying allele 1 in both the groups. These data suggest that the coal dust-induced release of TNF-alpha from monocytes may be a useful biomarker of CWP.     

CYP 17 and estrogen receptor α gene polymorphisms: association with breast cancer susceptibility and clinicopathological parameters in a cohort of Egyptian patients

The association between exposure to endogenous and exogenous steroid hormones and breast cancer (BC) risk is well established. The aim of this study was to examine whether Cytochrome P450 (CYP)17 -34T>C and estrogen receptor (ER)α XbaI gene polymorphisms might influence endogenous estrogen hormone level. Also, we aimed to examine the potential association between these polymorphisms and BC risk, as well as some clinicopathological parameters in BC patients. Eighty-one Egyptian female subjects were recruited; 41 pathologically confirmed BC patients and 40 apparently healthy, age-matched female control subjects. Serum estradiol level was assayed using radioimmunoassay. Polymerase chain reaction–restriction fragment length polymorphism technique was used for detection of CYP 17 -34T>C and ERα-XbaI polymorphisms. Serum estradiol level did not show statistically significant difference when compared between the different CYP17 and ERα genotypes in controls (p?=?0.088 and 0.241, respectively). No significant association between CYP17 and ER α gene polymorphisms and BC risk was encountered. There was a statistically significant association between ER α genotypes in overall BC cases with each of age at menarche, p?=?0.024, age at diagnosis, p?=?0.011, and nodal involvement, p?=?0.037, and between nodal number and ER α genotypes in the premenopausal BC group, p?=?0.038. In conclusion, CYP17 and ERα genotypes did not influence serum estradiol level. No statistically significant association was found between CYP17 -34T>C and ERα XbaI gene polymorphisms and breast cancer risk in Egyptian women. ER α gene may have an association with some clinicopathological parameters in breast cancer in Egyptian patients.     

Preliminary genetic imaging study of the association between estrogen receptor-α gene polymorphisms and harsh human maternal parenting

A failure of neural changes initiated by the estrogen surge in late pregnancy to reverse the valence of infant stimuli from aversive to rewarding is associated with dysfunctional maternal behavior in nonhuman mammals. Estrogen receptor-α plays the crucial role in mediating these neural effects of estrogen priming. This preliminary study examines associations between estrogen receptor-α gene polymorphisms and human maternal behavior. Two polymorphisms were associated with human negative maternal parenting. Furthermore, hemodynamic responses in functional magnetic resonance imaging to child stimuli in neural regions associated with social cognition fully mediated the association between genetic variation and negative parenting. This suggests testable hypotheses regarding a biological pathway between genetic variants and dysfunctional human maternal parenting.     

The role of glucocorticoid in SIRPα and SHP-1 gene expression in AIHA patients

The aim of this work was to evaluate the regulation of SIRPα, an inhibitory phagocyte receptor, and the phosphatase SHP-1 in monocytes of patients with autoimmune hemolytic anemia, and the role of dexamethasone on SIRPα and SHP-1 gene expression and erythrophagocytosis in vitro. SIRPα and SHP-1 expression was higher in monocytes from AIHA patients compared with normal, returning to normal after glucocorticoid therapy. SIRPα and SHP-1 mRNA expression was upregulated in healthy monocytes treated with dexamethasone compared with basal; however, the erythrophagocytic ability was not altered. Our results point to a minor role of SIRPα and SHP-1 in determining AIHA.     

Relationship of IL-1 and TNF-α polymorphisms with Helicobacter pylori in gastric diseases in a Brazilian population

It is well known that the risk of development of gastric cancer (GC) in Helicobacter pylori-infected patients depends on several factors. Thus, the aim of this study was to investigate the effect of proinflammatory cytokine gene polymorphisms for IL-1β, IL-1RN and TNF-α on the development of GC in a Brazilian population. A total of 202 biopsies obtained from Brazilian patients with chronic gastritis and GC were included in the study. Infection with H. pylori cagA⁺ was determined by the polymerase chain reaction (PCR) as previously described. IL-1β, IL-1RN and TNF-α polymorphism genotyping was performed by restriction fragment length polymorphism PCR. Associations between gene polymorphisms, clinical diseases and virulence markers were evaluated using either the X² test or the Fisher exact test. Our results demonstrated that the IL-1β -511 C/C and IL-1β -511 C/T alleles were associated with chronic gastritis in H. pylori-positive patients (P = 0.04 and P = 0.05, respectively) and the IL-1β -511 C/C genotype was associated with GC (P = 0.03). The frequency of IL-1RN alleles from patients with chronic gastritis and GC indicated that there was no difference between the genotypes of the groups studied. Similar results were found for TNF-α -308 gene polymorphisms. Our results indicate that the IL-1β -511 C/C and C/T gene polymorphisms are associated with chronic gastritis and GC development in H. pylori-infected individuals.     

Association analysis of Toll-like receptor 7 gene polymorphisms and Behçet's disease in Japanese patients

Action of Toll-like receptors (TLRs) is deeply associated with defense mechanisms of the innate and adaptive immune responses to microbial pathogens. There have been reports of genetic polymorphisms within the TLR7 gene being closely related to a variety of inflammatory and infectious diseases. Behçet's disease (BD) is an autoinflammatory disease, and the pathogenesis has yet to be fully discovered. We investigated whether polymorphisms of Toll-like receptor 7 (TLR7) are associated with BD by analyzing the frequency of eight single nucleotide polymorphisms (SNPs) within 200 Japanese BD patients and 102 randomized controls. We genotyped nine SNPs in the TLR7 gene and assessed the allele/genotype diversity between cases and controls for all SNPs. In all eight SNPs, statistically significant differences were not observed between cases and controls.     

FCεRI gene promoter polymorphisms and total IgE levels in susceptibility to atopic dermatitis in Korea

IgE-dependent activation of mast cells and basophils through the high-affinity IgE receptor (FcεRI) is involved in the pathogenesis of allergen-induced immune responsiveness in atopic diseases like atopic dermatitis (AD). We sought to determine FcεRI gene polymorphisms are associated with AD in Korean patients, and analyzed the relevance of FcεRI gene polymorphisms and serum IgE levels. We conducted a case-control association analysis (175 patients and 56 controls) of Korean subjects. Genotyping was performed using the TaqMan fluorogenic 5' nuclease assay, and serum levels of IgE were measured using a fluorescence enzyme immunoassay. We found that there were no significant relationships between FcεRI and AD, although there were trends towards an association between the 66T>C (rs2251746) polymorphism and total serum IgE levels in the Korean AD patients. In conclusion, while the 66T>C (rs2251746) of the FcεRIα polymorphism may be linked to AD and higher serum IgE levels, polymorphisms in the FcεRIβ gene did not confer susceptibility to AD in our patient sample.     

Effect of Thalidomide on the Expression of TNF-α m-RNA and Synthesis of TNF-α in Cells from Leprosy Patients with Reversal Reaction

Hypersensitivity reactions called reversal reaction (RR) and erythema nodosum leprosum (ENL) occur in leprosy. They are characterized by an increase in tumor necrosis factor-alpha (TNF-α). Thalidomide is an effective treatment for ENL but not RR. Its effectiveness in ENL is attributed to inhibition of TNF-α, and this does not explain its failure to treat RR. We assessed thalidomide's effect on TNF-α in RR. Mononuclear cells from RR and non-RR patients and healthy individuals were treated with thalidomide and M.leprae (AFB), a cytosol fraction of M. leprae or Dharmendra lepromin. Thalidomide suppressed TNF-α, but when some RR patients' cells were stimulated with AFB, it enhanced TNF-α.     

Impact of IL28B gene polymorphisms rs8099917 and rs12980275 on response to pegylated interferon-α/ribavirin therapy in chronic hepatitis C genotype 4 patients

Host genetic factors may predict the outcome and treatment response in hepatitis C virus (HCV) infection. One of these factors is the single nucleotide polymorphisms of the interleukin 28B (IL28B) gene. We sought to evaluate the outcome of pegylated interferon and ribavirin therapy in association with IL-28B rs8099917 and rs12980275 in patients infected with HCV genotype 4. A total of 180 patients with chronic hepatitis C were selected from Egyptians who have received combined therapy with pegylated interferon and ribavirin for 6 months and their response was evaluated after follow-up at 0, 6, 12, 24 and 48 weeks from the beginning of the therapy. Blood samples were collected from responders and non-responders. Genomic DNA was extracted from whole blood and genotyping was carried out by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Our results showed that TT genotype of rs8099917 was associated with higher sustained viral response (SVR) rates and G allele represented a risk factor for failure of response (OR = 3.7, CI = 1.8:7.64) while rs12980275 was not significantly associated with SVR in genotype 4 Egyptian patients. The determination of IL-28B SNPs may be useful in enhancing correct prediction of SVR achievement in treating this group of genotype 4 patients.     

Impact of Three Anti-TNFα Biologics on Existing and Emergent Autoimmunity in Rheumatoid Arthritis and Spondylarthropathy Patients

OBJECTIVE: The objective of this study was to analyze the effects of 3 anti-TNFalpha agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients. METHODS: First-time anti-TNFalpha biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1-2 years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually. RESULTS: ANA appeared or ANA and anti-dsDNA titers increased significantly (P < 0.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (P = 0.003), but independently of the anti-TNFalpha used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18 months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics. CONCLUSION: This is the first study that has evaluated the impact of three TNFalpha blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.