Dataset Information

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

ABSTRACT: 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 TNF?. 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 (?2-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-?B 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.

SUBMITTER: Zhang B

PROVIDER: S-EPMC6530917 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Identification of functional missense single-nucleotide polymorphisms in <i>TNFAIP3</i> in a predominantly Hispanic population.

Zhang Bing B Naomi Nakamura Brooke B Perlman Aryeh A Alipour Omeed O Abbasi Sadeea Qureshi SQ Sohn Peter P Gulati Alakh A Moore Graham G Hwang Caroline C Sheibani Sarah S Zarchy Thomas T Shao Ling L

Journal of clinical and translational science 20181201 6

<h4>Background</h4>Tumor necrosis factor alpha-induced protein 3 (<i>TNFAIP3</i>) is a multifunctional ubiquitin binding and editing enzyme that regulates inflammation. Genetic studies have implicated polymorphisms within the <i>TNFAIP3</i> 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 <i>TNFAIP3</i> gene and an associated point mutation from the Illumina array among a p ...[more]

PMID: 31131138

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Project description: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.

Dataset Information

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

Publications

Identification of functional missense single-nucleotide polymorphisms in <i>TNFAIP3</i> in a predominantly Hispanic population.

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