RESUMO
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.
RESUMO
The capacity for colonoscopy is limited and a method to prioritize patients for diagnostic colonoscopy is needed in health care centers. A retrospective cross-sectional cohort study was carried out in county and community endoscopy centers, which included 1,065 county and 279 community patients aged > or = 40 years undergoing diagnostic colonoscopy. We constructed a risk profile for proximal advanced neoplasms on diagnostic colonoscopy at the county center based on the size of the regression coefficients for independent risk factors from logistic regression. An advanced neoplasm was defined as one of size > or = 1 cm or containing villous histology, high-grade dysplasia, or cancer. In our county colonoscopy population (n = 929 after exclusions), the stepwise logistic regression analysis identified age > or = 60 years (adjusted odds ratio [AOR]: 2.60; 95% confidence interval [CI]:1.14, 6.14), iron deficiency anemia (AOR: 4.74; 95% CI: 2.07, 11.34), and an advanced neoplasm in the recto-sigmoid (AOR: 6.01; 95% CI: 2.02, 16.00) as the statistically significant predictors of an advanced proximal neoplasm. In the county population, the prevalence rates of an advanced proximal neoplasm and proximal high-grade dysplasia/cancer in the low-risk group were 0.71% (95% CI: 0.15, 2.05) and 0.24% (95% CI: 0.01, 1.31), respectively. Avoiding colonoscopy in this group would increase the capacity for colonoscopy by 46% in the higher risk groups. In a disparate community population (n = 237 after exclusions), this scoring system had a goodness-of-fit test showing high concordance (P = 0.51). This clinical profile stratified the risk for an advanced neoplasm proximal to the sigmoid in patients undergoing diagnostic colonoscopy. It identified a large subset of low-risk patients.