Associations between <scp>TNFAIP3</scp> gene polymorphisms and systemic lupus erythematosus risk: an updated meta‐analysis

Zhang, M.-Y.; Yang, Xiao; Pan, Hai‐Feng; Ye, D.-Q.

doi:10.1111/tan.12908

Cited by 14 publications

(11 citation statements)

References 44 publications

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“…Two tightly linked variants, rs719149 and rs719150, associated with lower levels of TNFAIP3 in AxSpA cases only but not controls ( p = 0.016 for SpA status). Variants rs5029937, rs5029939, and F127C have previously been reported to associate with RA and SLE and showed a trend toward lower levels in this study (45, 46). However, none of the individual variants identified were statistically significant following correction for multiple variant testing.…”

Section: Resultssupporting

confidence: 61%

“…Some of the TNFAIP3 variants found in our population have been reported in other diseases: rs5029937 and F127C with RA and SLE, rs5029939 with SLE and systemic sclerosis, and F127C and rs610604 with psoriasis (45, 46, 60, 61). However, despite the increasing implication of TNFAIP3 in multiple autoimmune and inflammatory diseases, little information is available regarding how TNFAIP3 variants modulate gene expression.…”

Section: Discussionsupporting

confidence: 58%

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Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

Liu

et al. 2017

Front. Immunol.

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ObjectiveTumor necrosis factor alpha-induced protein 3 (TNFAIP3) is an anti-inflammatory protein implicated in multiple autoimmune and rheumatologic conditions. We hypothesized that lower levels of TNFAIP3 contributes to excessive cytokine production in response to inflammatory stimuli in axial spondyloarthritis (AxSpA). A further aim was to determine the immune signaling and genetic variation regulating TNFAIP3 expression in individual subjects.MethodsBlood-derived macrophages from 50 AxSpA subjects and 30 healthy controls were assessed for TNFAIP3 expression. Cell lysates were also analyzed for NF-κB, mitogen-activated protein (MAP) kinase and STAT3 phosphorylation, and supernatants for cytokine production. Coding and regulatory regions in the TNFAIP3 gene and other auto-inflammation-implicated genes were sequenced by next-generation sequencing and variants identified.ResultsMean TNFAIP3 was significantly lower in spondyloarthritis macrophages than controls (p = 0.0085). Spondyloarthritis subject macrophages correspondingly produced more TNF-α in response to lipopolysaccharide (LPS, p = 0.015). Subjects with the highest TNFAIP3 produced significantly less TNF-α in response to LPS (p = 0.0023). Within AxSpA subjects, those on TNF blockers or with shorter duration of disease expressed lower levels of TNFAIP3 (p = 0.0011 and 0.0030, respectively). TNFAIP3 expression correlated positively with phosphorylated IκBα, phosphorylated MAP kinases, and unstimulated phosphorylated STAT3, but negatively with LPS or TNF-α-stimulated fold induction of phosphorylated STAT3. Further, subjects with specific groups of variants within TNFAIP3 displayed differences in TNFAIP3 (p = 0.03–0.004). Nominal pQTL associations with genetic variants outside TNFAIP3 were identified.ConclusionOur results suggest that both immune functional and genetic variations contribute to the regulation of TNFAIP3 levels in individual subjects. Decreased expression of TNFAIP3 in AxSpA macrophages correlated with increased LPS-induced TNF-α, and thus, TNFAIP3 dysregulation may be a contributor to excessive inflammatory responses in spondyloarthritis subjects.

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Section: Resultssupporting

confidence: 61%

Section: Discussionsupporting

confidence: 58%

Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

Liu

et al. 2017

Front. Immunol.

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“…Sequencing the exon regions of TNFAIP3 revealed two SNPs in close proximity to the OTU catalytic site. While rs2230926:T>G has been well-studied in the context of autoimmune diseases [39,49,50], rs146534657:A>G is poorly-characterized with only one report linking it to poor outcome among Chinese RA patients [34]. The function of this SNP in altering the amino acid directly adjacent to the catalytic cysteine within the OTU and its prevalence among Hispanics highlight clinical implications among this population.…”

Section: Discussionmentioning

confidence: 99%

Identification of functional missense single-nucleotide polymorphisms in TNFAIP3 in a predominantly Hispanic population

Zhang

Nakamura

Perlman

et al. 2018

J. Clin. Trans. Sci.

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Background:Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is a multifunctional ubiquitin binding and editing enzyme that regulates inflammation. Genetic studies have implicated polymorphisms within the TNFAIP3 locus to the development of numerous immune-related diseases. This study evaluated the frequencies of single-nucleotide polymorphism (SNPs) within the exonic regions of the TNFAIP3 gene and an associated point mutation from the Illumina array among a predominantly Hispanic cohort.Methods:Genomic DNA was obtained from 721 participants and sequencing of all TNFAIP3 exons and an intergenic point mutation (rs6920220) was performed. In-vitro functional assessment was performed by transfecting mutated TNFAIP3 constructs into TNFAIP3 knockout cells containing the NF-kB luciferase reporter and stimulating with TNFα. Comparative statistics were performed with Student’s t-test for continuous variables and chi-squared test for categorical variables.Results:Sequencing revealed two missense SNPs, rs146534657:A>G and rs2230926:T>G, both within exon 3 of TNFAIP3, which encodes the protein’s deubiquitinating enzymatic domain. Frequencies of all three point mutations differed significantly across racial groups (χ2-test, P = 0.014 to P < 0.001). Compared to Caucasians, rs146534657:A>G was overrepresented among Hispanics (odds ratio (OR) [95% CI] 4.05 [1.24−13.18]), and rs2230926:T>G was more prevalent among African-Americans (OR [95% CI] 3.65 [1.58−8.43]). In-vitro assays confirm rs146534657:A>G and rs2230926:T>G decrease the ability of TNFAIP3 to abrogate NF-κB activation by 2-fold (P < 0.01) and 1.7-fold (P < 0.01), respectively.Conclusions:This study reports the frequency of rs146534657:A>G among Hispanics and is the first to evaluate its potential physiologic impact, establishing a basis for future research as a potential biomarker among this population.

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“…A meta-analysis study from 10 casecontrol research revealed that rs5029937 polymorphism increased the risk of RA among Caucasians (21). Furthermore previous studies demonstrated that this variant is associated with SLE in Europeans and Asian populations (24,32). In the present study, we assessed the possible association between SNP rs5029937 (G>T) in the TNFAIP3 gene with RA risk in the Iranian population for the first time.…”

Section: Introductionmentioning

confidence: 89%

Single nucleotide polymorphism rs5029937 in TNFAIP3 gene is correlated with risk of rheumatoid arthritis

Pakzad

Yousefisadr

Karimzadeh

et al. 2021

mjiri

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Studies have shown that TNFAIP3 is fundamental for regulating inflammation by dismissing TNF-induced NFKB responses through tumor necrosis factor receptor (TNFR), TLR, IL1R and NOD2. Variations in the TNFAIP3 gene, as a key regulator of inflammatory signaling pathways, seem to dramatically contribute to autoimmunity. →What this article adds:Our results demonstrate that combination of TT+TG compared with the GG genotype in rs5029937 polymorphism increased the risk of disease. On the other hand, individuals with allele T were more frequently affected with RA than subjects with G allele.

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Associations between TNFAIP3 gene polymorphisms and systemic lupus erythematosus risk: an updated meta‐analysis

Cited by 14 publications

References 44 publications

Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

Identification of functional missense single-nucleotide polymorphisms in TNFAIP3 in a predominantly Hispanic population

Single nucleotide polymorphism rs5029937 in TNFAIP3 gene is correlated with risk of rheumatoid arthritis

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