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

<jats:title>Abstract</jats:title><jats:sec id="S2059866119000037_as1"><jats:title>Background:</jats:title><jats:p>Tumor necrosis factor alpha-induced protein 3 (<jats:italic>TNFAIP3</jats:italic>) is a multifunctional ubiquitin binding and editing enzyme that regulates inflammation. Genetic studies have implicated polymorphisms within the <jats:italic>TNFAIP3</jats:italic> 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 <jats:italic>TNFAIP3</jats:italic> gene and an associated point mutation from the Illumina array among a predominantly Hispanic cohort.</jats:p></jats:sec><jats:sec id="S2059866119000037_as2"><jats:title>Methods:</jats:title><jats:p>Genomic DNA was obtained from 721 participants and sequencing of all <jats:italic>TNFAIP3</jats:italic> exons and an intergenic point mutation (rs6920220) was performed. <jats:italic>In-vitro</jats:italic> functional assessment was performed by transfecting mutated <jats:italic>TNFAIP3</jats:italic> constructs into <jats:italic>TNFAIP3</jats:italic> knockout cells containing the NF-kB luciferase reporter and stimulating with TNFα. Comparative statistics were performed with Student’s <jats:italic>t</jats:italic>-test for continuous variables and chi-squared test for categorical variables.</jats:p></jats:sec><jats:sec id="S2059866119000037_as3"><jats:title>Results:</jats:title><jats:p>Sequencing revealed two missense SNPs, rs146534657:A>G and rs2230926:T>G, both within exon 3 of <jats:italic>TNFAIP3</jats:italic>, which encodes the protein’s deubiquitinating enzymatic domain. Frequencies of all three point mutations differed significantly across racial groups (<jats:italic>χ</jats:italic><jats:sup>2</jats:sup>-test, <jats:italic>P</jats:italic> = 0.014 to <jats:italic>P</jats:italic> < 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]). <jats:italic>In-vitro</jats:italic> assays confirm rs146534657:A>G and rs2230926:T>G decrease the ability of <jats:italic>TNFAIP3</jats:italic> to abrogate NF-κB activation by 2-fold (<jats:italic>P</jats:italic> < 0.01) and 1.7-fold (<jats:italic>P</jats:italic> < 0.01), respectively.</jats:p></jats:sec><jats:sec id="S2059866119000037_as4"><jats:title>Conclusions:</jats:title><jats:p>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.</jats:p></jats:sec>