TNFAIP3 Research Articles

Single nucleotide polymorphisms in TNFAIP3 were associated with the risks of rheumatoid arthritis in northern Chinese Han population.

BackgroundRheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic destructive inflammation in synovial joints. It is well known that genetic and environmental risk factors and their interaction contribute to RA pathogenesis. This study aimed to investigate the association between the critical polymorphisms in the tumor necrosis factor α (TNFα)-induced protein 3(TNFAIP3) gene and the risk of RA in a large northern Chinese Han population.MethodsA case–control study of 1280 RA patients and 1280 matched healthy controls was conducted.ResultsThis study showed that carriers of the rs2230926 TG genotype or rs10499194 CT genotype had an increased risk for RA compared with those carrying the wild genotype (rs2230926: OR = 1.48, 95% CI = 1.17-1.86, p = 0.001; rs10499194: OR = 2.00, 95% CI = 1.46-2.74, p < 0.001). The combined rs2230926TG/GG or rs10499194 CT/TT were associated with an increased risk of RA (ORs were 1.50 and 2.01, 95% CIs were 1.19-1.88 and 1.47-2.74, respectively, both p < 0.001). There was not significant association between rs13207033 polymorphism and RA risk. Subset analysis stratified to gender showed that the increased risks were significant among the genotypes TG, TG/GG of rs2230926 and CT, CT/TT of rs10499194 and the corresponding ORs were 1.42 (95% CI = 1.10-1.83, p = 0.006), 1.44(95% CI = 1.12-1.85, p = 0.004), 1.52(95% CI = 1.05-2.20, p = 0.026) and 1.52(95% CI = 1.06-2.19, p = 0.023) in the female population. Stratified analyses by age found that rs2230926(TG, TG/GG) and rs10499194(CT, CT/TT) polymorphisms were associated with RA risks in population ≤53 years old and among >53 years old only rs10499194(CT, TT, CT/TT) polymorphism had significant results. The interaction analysis suggested that individuals with both risk genotypes of the two SNPs have a higher elevated risk of RA than those with only one of them (ORs were 3.44 compared to 1.74 and 1.35). The haplotype results showed that individuals with the rs2230926G-rs13207033G-rs10499194C haplotype were associated with increased risks of RA (OR = 1.37, 95% CI = 1.08-1.74, p = 0.010).ConclusionsRs10499194 and rs2230926 polymorphisms in the TNFAIP3 gene region may be susceptibility factors for rheumatoid arthritis in the northern Chinese Han population.

Monocytes and CD4 + T cells contribution to the under-expression of NR4A2 and TNFAIP3 genes in patients with multiple sclerosis

We recently found a gene signature for multiple sclerosis (MS) that reverted to normal during pregnancy in MS patients and included NR4A2 and TNFAIP3, key molecules in anti-inflammatory processes. Here we focus on the expression levels of these two genes in monocytes and CD4+ T cells from healthy controls and treatment-naïve RRMS patients. Our findings show that monocytes play a key role in the dysregulated anti-inflammatory response, being the expression of both genes down-regulated in these cells in RRMS patients with respect to healthy individuals. CD4+ T cells seem to have only a marginal part, because we can observe only a slight down-regulation in NR4A2.

Polymorphisms of the TNFAIP3 region and Graves' disease

Autoimmune thyroid disease (AITD) is a multifactorial organ-specific autoimmune disorder, and both genetic susceptibility and environmental factors are involved in its etiology. TNFAIP3 encodes the ubiquitin-modifying enzyme (A20), a key regulator of inflammatory signaling pathways. The aim of the present study was to evaluate the association between TNFAIP3 gene polymorphisms and AITD in Chinese Han population. Three single nucleotide polymorphisms (SNPs) in TNFAIP3 gene locus (rs598493, rs610604 and rs661561) were detected in a set of 667 patients with AITD and 301 controls in Han Chinese population using the Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform. Compared with those of the controls, the frequencies of GG genotype of rs598493, the AA genotype of rs610604, the allele G and GG genotype of rs661561 were significantly increased in Graves' disease (GD) patients. However, the frequencies of AG genotype of rs598493 and AC genotype of rs610604 were significantly decreased in GD patients. The ATC haplotype (rs598493, rs661561 and rs610604) was associated with a decreased risk of GD. No significant differences in the three SNPs were observed between HT patients and controls. Our study shows a clear association between the polymorphisms of TNFAIP3 gene and GD, not HT, suggesting that TNFAIP3 gene is likely to be a genetic susceptibility factor to GD.

TNFAIP3 gene polymorphisms associated with differential susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Korean population

We investigated the relationship between polymorphisms in the TNF-a-induced protein 3 (TNFAIP3) gene and genetic susceptibility to SLE and RA in the Korean population. The present case control study included 422 patients with RA, 133 patients with SLE and 422 healthy controls. Genotyping for TNFAIP3 gene polymorphisms rs5029941 (C>T), rs2230926 (T>G), rs5029930 (C>A), rs5029937 (G>T) and rs5029939 (G>C) in TNFAIP3 gene polymorphisms was performed. The status of RA-related autoantibodies, including RF and anti-CCP, in RA and the presence of arthritis and nephritis in SLE were assessed. Significantly different frequencies of minor alleles in two TNFAIP3 polymorphisms were found in patients with SLE compared with healthy controls [odds ratio (OR) 2.13, 95% CI 1.25, 3.65, P= 0.02 for rs5029937; OR 2.17, 95% CI 1.27, 3.72, P= 0.01 for rs5029939). Moreover, patients with SLE showed different frequencies of haplotypes compared with healthy controls (P<0.001). However, no association was found between RA susceptibility and TNFAIP3 polymorphisms (P= 0.28). Interactions between RA-related autoantibody status and TNFAIP3 polymorphisms were not associated with RA susceptibility. Interestingly, arthritis in patients with SLE was marginally associated with TNFAIP3 polymorphisms (P= 0.04). The results suggest that TNFAIP3 gene polymorphisms are associated with differential susceptibility to SLE and RA in the Korean population. The relationship between TNFAIP3 gene polymorphisms and RA susceptibility may be dependent on ethnic background.

Association of polymorphisms in TNFAIP3 and TNIPI genes with predisposition to the development of psoriasis in the Russian population

Goal. To study polymorphisms in TNFAIP3 (rs610604) and TNIPI (rs17728338) genes in a sample of psoriasis patients and healthy volunteers from the Russian Federation. Materials and methods. By using allele specific hybridization methods in the form of real-time PCR and RFLP assay (Restriction Fragment Length Polymorphism), single-nucleotide polymorphisms of fragments of the following genes associated with predisposition to the development of psoriasis were studied in whole blood samples taken from psoriasis patients (n = 286) and healthy volunteers (n = 89): TNFAIP3 (rs610604) and TNIPI (rs17728338). Results. Psoriasis patients had a reliable increase in the frequency of the A/C heterozygous genotype of rs610604 polymorphism of the TNFAIP3 gene and A allele of rs17728338 polymorphism of the TNIP1 gene (A/G and A/A genotypes), which makes it possible to treat carriers of these genotypes as people with predisposition to the development of psoriasis, and to treat A/C genotypes of rs610604 polymorphism and A/G and A/A genotypes of rs17728338 polymorphism as predictors of the development of psoriasis in the Russian population. Conclusion. these data broaden the perception of genetic factors associated with the development of psoriasis in persons from the Russian population.

Association of Genes in the NF‐κB Pathway with Antibody‐Positive Primary Sjögren's Syndrome

Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-κB in primary SS. NF-κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB and of IKBKE (IKKε), which is an NF-κB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n = 868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P = 3.4 × 10(-5) , OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and P = 1.3 × 10(-3) , OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P = 5.7 × 10(-3) , OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.

Analysis of Gender Differences in Genetic Risk: Association of TNFAIP3 Polymorphism with Male Childhood-Onset Systemic Lupus Erythematosus in the Japanese Population

BackgroundSystemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.Methodology/Principal FindingsThe 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P<0.05).ConclusionsAssociations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

OP0023 Germinal and Somatic Genetic Variants of TNFAIP3 Promote Lymphomagenesis Process Complicating Primary Sjögren’s Syndrome

BackgroundThe pathophysiology of lymphomas in auto immune disease (AID) involves persistent inflammation and activation of autoimmune B cells leading to NF-kB activation. The TNFAIP3 gene encodes the A20 protein, a...

Association studies of TNFSF4, TNFAIP3 and FAM167A-BLK polymorphisms with primary Sjogren’s syndrome in Han Chinese

Single-nucleotide polymorphisms (SNPs) in the TNFSF4, TNFAIP3 and FAM167A-BLK genes have been associated with several autoimmune diseases. Associations of TNFSF4 and FAM167A-BLK with primary Sjogren's syndrome (pSS) have also been described in a Caucasian population. However, it remains unknown whether polymorphisms of TNFSF4, TNFAIP3 and FAM167A-BLK are associated with pSS in Han Chinese. This study aimed to determine whether SNPs in TNFSF4, TNFAIP3 or FAM167A-BLK genetically predispose a Chinese Han population to pSS. Ten SNPs in the TNFSF4 region (rs1234315, rs2205960, rs844648 and rs704840), the TNFAIP3 gene (rs5029939 and rs2230926) and the FAM167A-BLK region (rs7812879, rs2254546, rs2618479 and rs2248932) were genotyped in a cohort of 555 pSS patients and 597 healthy controls, by using the Sequenom MassArray system. Weak associations were observed when the SNPs in TNFSF4 (rs2205960, rs844648 and rs704840) and FAM167A-BLK (rs7812879, rs2254546 and rs2618479) were directly analyzed or analyzed under dominant model between pSS and controls (all P<0.05). However, when Bonferroni correction was applied to the multiple comparisons, all of the associations vanished, except for rs7812879 (Pa=0.045). The frequencies of alleles, genotypes and haplotypes of TNFAIP3 SNPs and rs2248932 of FAM167A-BLK were not significantly different between the pSS patients and controls. No epistatic interactions were found to exist between the SNPs examined. Unlike the SNPs in TNFAIP3 and TNFSF4, rs7812879 in FAM167A-BLK imparts susceptibility to pSS in a Han Chinese population. The differential genetic risk profiles from other autoimmune diseases may indicate differential molecular mechanisms underlying pSS pathogenesis in this group.

TNFAIP3 Gene Polymorphisms in a Chinese Han Population with Vogt–Koyanagi–Harada Syndrome

BackgroundThis study was performed to evaluate the potential association of TNFAIP3 polymorphisms with Vogt–Koyanagi–Harada (VKH) disease in a Chinese Han population.Methodology/Principal FindingsFive single-nucleotide polymorphisms (SNPs), rs10499194, rs610604, rs7753873, rs5029928 and rs9494885 of TNFAIP3 were genotyped in 834 VKH disease patients and 1415 healthy controls using a PCR-restriction fragment length polymorphism assay. An increased frequency of the C allele and CT genotype for rs9494885 were found in VKH patients in the Guangzhou and Chongqing cohorts (pc = 0.015, OR = 1.6, pc = 0.036, OR = 1.7; pc = 2.36×10−4, OR = 1.5, pc = 0.012, OR = 1.5, respectively). Meanwhile, a decreased frequency of the TT genotype for rs9494885 was observed in VKH patients in the Guangzhou and Chongqing cohorts (pc = 0.026, OR = 0.6, pc = 0.0074, OR = 0.7, respectively). The combined analysis showed that a significantly increased prevalence of the rs9494885 TC genotype and C allele were found in VKH disease patients compared with controls (pc = 2.26×10−5, OR = 1.7; pc = 1.09× 10−5, OR = 1.6, respectively). The frequency of the TT genotype of rs9494885 was markedly lower in VKH disease patients as compared with that in controls (pc = 1.12×10−5, OR = 0.6; pc = 1.09×10−5, OR = 0.6, respectively). No association was found between rs10499194, rs610604, rs7753873 and rs5029928 polymorphisms and VKH disease. To our knowledge this is the first report describing the association of a TNFAIP3 gene polymorphism with VKH disease in a Chinese Han population.Conclusions/SignificanceThe results suggest that the rs9494885 TC genotype and C allele may be predisposing factors to VKH disease, whereas the rs9494885 TT genotype and T allele may provide protection against this disease.

Pharmacogenetics: Reality or Dream in Predicting the Response to TNF-α Inhibitor Treatment?

Background: The ongoing progresses in the knowledge of the pathogenic mechanisms of various immunemediated or inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, ankylosing spondylitis, disseminated granuloma annulare, psoriasis and/or psoriatic arthritis, and the availability of innovative biotechnological approaches have lead to the development of new drugs which add to conventional treatments. There are five TNF-α inhibitors available for clinical use including anti-TNF-α monoclonal antibodies (infliximab, adalimumab, golimumab and certolizumab pegol) and a fusion protein that acts as a “decoy receptor” for TNF-α (etanercept). Pharmacogenetics has the potential of increasing drug efficiency by identifying genetic factors responsible for lack response or toxicities to TNF-α inhibitors. Methods: We analyzed the most recent studies in the literature relating to different genetic polymorphisms and their potential association with the therapeutic response to TNF-α inhibitors. Results: SNP at position -308 of the TNF-α promoter genes and particularly the -308 G/G genotype and HLA-DRB1-encoding shared epitope (allele *0404 and allele *0101) may predict a better response to etanercept. Polymorphisms of TNFR1 and TNFR2 decrease response to infliximab. By contrast, FCGR3A-158 polymorphism seems to favor the response to infliximab. G allele of SNP rs610604 located in the TNFAIP3 gene and its haplotype with the T allele of rs2230926 could be considered as markers of good response to etanercept, infliximab and adalimumab. Conclusion: Most of these studies are often small and not sufficiently powered to detect an effect and often examines only the effects of a single SNP, while it would be more useful to analyze more haplotypes in contemporary in the same patients. Candidate genes may be in linkage with other loci, thus, having a true influence upon the pharmacology of TNF-α inhibitors. Further studies are needed before a pharmacogenetic approach may be applicable in daily clinical therapeutic practice.

Deletion of the TNFAIP3/A20gene detected by FICTION analysis in classical Hodgkin lymphoma

BackgroundThe TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in the negative regulation of NF-κB signaling, is frequently inactivated by gene deletions/mutations in a variety of B-cell malignancies. However, the detection of this in primary Hodgkin lymphoma (HL) specimens is hampered by the scarcity of Hodgkin Reed-Sternberg (HR-S) cells even after enrichment by micro-dissection.MethodsWe used anti-CD30 immunofluorescence with fluorescence in-situ hybridization (FISH) to evaluate the relative number of TNFAIP3/CEP6 double-positive signals in CD30-positive cells.ResultsFrom a total of 47 primary classical Hodgkin lymphoma (cHL) specimens, 44 were evaluable. We found that the relative numbers of TNFAIP3/CD30 cells were distributed among three groups, corresponding to those having homozygous (11%), heterozygous (32%), and no (57%) deletions in TNFAIP3. This shows that TNFAIP3 deletions could be sensitively detected using our chosen methods.ConclusionsComparing the results with mutation analysis, TNFAIP3 inactivation was shown to have escaped detection in many samples with homozygous deletions. This suggests that TNFAIP3 inactivation in primary cHL specimens might be more frequent than previously reported.

TNFAIP3 Facilitates Degradation of Microbial Antigen SEB in Enterocytes

Background and AimsThe enterocytes have the potential to absorb noxious substances, such as microbial products, from the gut lumen. How the enterocytes process the substances to harmless materials is not fully understood. This study aims to elucidate the role of ubiquitin E3 ligase TNFAIP3 (TNFAIP3) in facilitating the degradation of endocytic microbial products in enterocytes.MethodsHuman intestinal epithelial cell line, HT-29 cells, was cultured to monolayers using as an in vitro model to observe the endocytosis and degradation of microbial products, Staphylococcal enterotoxin B (SEB) in epithelial cells. The RNA interference was employed to knock down the TNFAIP3 gene in HT-29 cells to observe the role of TNFAIP3 in the degradation of endocytic SEB. The role of TNFAIP3 in facilitating the endosome/lysosome fusion was observed by immunocytochemistry.ResultsUpon the absorption of SEB, the expression of TNFAIP3 was increased in HT-29 cells. Silencing the TNFAIP3 gene in HT-29 cells resulted in a large quantity of SEB to be transported across the HT-29 monolayers to the transwell basal chambers; the transportation was via the intracellular pathway. TNFAIP3 was required in the fusion of SEB-carrying endosomes and lysosomes.ConclusionsTNFAIP3 plays a critical role in the degradation of endocytic SEB in enterocytes.

Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer

Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

Role of nuclear factor-κB regulators TNFAIP3 and CARD11 in Middle Eastern diffuse large B-cell lymphoma

Aberrant nuclear factor-κB (NF-κB) regulation has been observed in many hematopoietic malignancies including diffuse large B-cell lymphoma (DLBCL). Considering the potential therapeutic utility of targeting NF-κB and its key modulators, we studied genetic alterations (mutations and amplifications) in TNFAIP3 and CARD11 genes in DLBCL samples. The incidence of CARD11 and TNFAIP3 mutations was 10.7% and 4.6%, respectively. Interestingly, CARD11 amplification was seen in a significant proportion of cases of DLBCL (23%) and was linked to NF-κB activation (p = 0.0142). Immunohistochemical analysis of DLBCL samples showed CARD11 overexpression and loss of TNFAIP3 in 17.7% (32/181) and 13.5% (24/178), respectively. Poor overall survival was noted in DLBCL harboring CARD11 gene amplification (p = 0.0491). Our study reports the incidence of TNFAIP3 and CARD11 alterations in Saudi DLBCL, a potentially unique ethnic group, and highlights for the first time the role of CARD11 gene amplification as a novel mechanism for NF-κB activation in Middle Eastern DLBCL.

Abstract 1154: Genetic variation in NFκB signaling pathway genes in colorectal cancer susceptibility and survival

Abstract PURPOSE: Genetic alterations in inflammatory genes are associated with chronic inflammatory bowel disease, a well-known risk factor for colorectal cancer (CRC). The purpose of this study was to investigate the association between alterations in inflammatory NFκB signaling pathway genes and CRC susceptibility and survival. EXPERIMENTAL DESIGN: Using 344 CRC cases and 793 randomly selected healthy individuals from southeastern Sweden, we examined seven polymorphisms in NFκB, TNFAIP3, NLRP3, CARD8 and TLR4 genes. Chi-square tests and multiple logistic regression analysis were used to test for associations between the SNPs and CRC susceptibility, while log-rank tests and Cox proportional hazard regression were used to examine the association between the SNPs and CRC-specific survival. Loss of heterozygosity and mutational analyses of TNFAIP3 were carried out in 137 and 79 tumors, respectively. RESULTS: Adjusted for age, gender and polypoid/ulcerative CRC phenotype, a panel of heterozygous and mutant TNFAIP3 (rs6920220), mutant NF B −94 ATTG ins/del and heterozygous NLRP3 (Q705K) was associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2 95% CI 2.5-10.9, P &amp;lt; 0.001). Continuous or partial LOH of 6q23.3, the location of the TNFAIP3 gene was detected in 17% of the colorectal tumors while mutations in TNFAIP3 were detected in two out of 79 colorectal tumors (2.5%). CONCLUSIONS: We propose TNFAIP3 as a novel tumor suppressor in CRC and also present evidence that a panel of the TNFAIP3 (rs6920220), NF B −94 ATTG ins/del and NLRP3 (Q705K) polymorphisms could be used as a prognostic marker to identify patients at high risk for rapid CRC progression and poor survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1154. doi:1538-7445.AM2012-1154

Evaluation of TNFAIP3 Gene Polymorphisms as Prognostic Markers in Complete Resected Only Surgically Treated Esophageal Cancer

Evaluation of TNFAIP3 Gene Polymorphisms as Prognostic Markers in Complete Resected Only Surgically Treated Esophageal Cancer

Confirmation of TNIP1 and IL23A as susceptibility loci for psoriatic arthritis

ObjectivesTo investigate a shared genetic aetiology for skin involvement in psoriasis and psoriatic arthritis (PsA) by genotyping single-nucleotide polymorphisms (SNPs), reported to be associated in genome-wide association studies of psoriasis,...

Loss of Braking Signals During Inflammation

In a recent genome-wide transcriptional analysis, we identified a gene signature for multiple sclerosis (MS), which reverted back to normal during pregnancy. Reversion was particularly evident for 7 genes: SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1, most of which encode negative regulators of inflammation. To corroborate dysregulation of genes, to evaluate the prognostic value of genes, and to study modulation of genes during different treatments. Comparison study. Italian referral center for MS. Quantitative polymerase chain reaction measurements were performed for 274 patients with MS and 60 healthy controls. Of the 274 patients with MS, 113 were treatment-naive patients in the initial stages of their disorder who were followed up in real-world clinical settings and categorized on the basis of disease course. The remaining 161 patients with MS received disease-modifying therapies (55 patients were treated with interferon beta, 52 with glatiramer acetate, and 54 with natalizumab) for a mean (SD) of 12 (2) months. Gene expression levels, relapse rate, and change in Expanded Disability Status Scale. We found a dysregulated gene pathway (P ≤ .006), with a downregulation of genes encoding negative regulators. The SOCS2, NR4A2, and TNFAIP3 genes were inversely correlated with both relapse rate (P ≤ .002) and change in Expanded Disability Status Scale (P ≤ .005). SOCS2 was modulated by both interferon beta and glatiramer acetate, TNFAIP3 was modulated by glatiramer acetate, and NR4A2 was not altered at all. No changes were induced by natalizumab. We demonstrate that there is a new molecular pathogenic mechanism that underlies the initiation and progression of MS. Defects in negative-feedback loops of inflammation lead to an overactivation of the immune system so as to predispose the brain to inflammation-sensitive MS.

B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice

AbstractThe ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose–dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.