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

• Published in: Journal of clinical and translational science 2018-12, Vol.2 (6), p.350-355
• Main Authors: Zhang, Bing, Naomi Nakamura, Brooke, Perlman, Aryeh, Alipour, Omeed, Abbasi, Sadeea Qureshi, Sohn, Peter, Gulati, Alakh, Moore, Graham, Hwang, Caroline, Sheibani, Sarah, Zarchy, Thomas, Shao, Ling
• Format: Article
• Language: English
• Subjects: A20; autoimmune; Basic and Preclinical Research; Deoxyribonucleic acid; DNA; DNA sequencing; Exons; Gastroenterology; Gene polymorphism; Genetic testing; Genetics; Genomes; Hispanic; Hispanic people; IBD; Immunology; Inflammation; Inflammatory bowel disease; Lupus; Medicine; Mutation; NF-kB; NF-κB protein; Point mutation; Population; Proteins; Psoriasis; Rheumatoid arthritis; Single-nucleotide polymorphism; SNP; Studies; Systematic review; TNFAIP3; Tumor necrosis factor-α; Ubiquitin
• ISSN: 2059-8661; 2059-8661
• DOI: 10.1017/cts.2019.3

Tumor necrosis factor alpha-induced protein 3 ( ) is a multifunctional ubiquitin binding and editing enzyme that regulates inflammation. Genetic studies have implicated polymorphisms within the 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 gene and an associated point mutation from the Illumina array among a predominantly Hispanic cohort. Genomic DNA was obtained from 721 participants and sequencing of all exons and an intergenic point mutation (rs6920220) was performed. functional assessment was performed by transfecting mutated constructs into 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. Sequencing revealed two missense SNPs, rs146534657:A>G and rs2230926:T>G, both within exon 3 of which encodes the protein's deubiquitinating enzymatic domain. Frequencies of all three point mutations differed significantly across racial groups (χ test, P=0.014 to PG 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]). assays confirm rs146534657:A>G and rs2230926:T>G decrease the ability of to abrogate NF-κB activation by 2-fold (P