An autoimmune disease-associated risk variant in the TNFAIP3 gene plays a protective role 1 in brucellosis that is mediated by the NF-kappa B signaling pathway 2

12 occurring (rs148314165 In this analysis, we conducted a genetic association study of the TT>A variants in 1209 controls 16 and in 150 patients with brucellosis, an infectious disease, and further assessed the role of the 17 variants in brucellosis. Our data demonstrated that the TT>A variants were correlated with cases 18 of brucellosis ( P = 0.002, OR = 0.34) and with individuals who had a positive serum 19 agglutination test (SAT ＞ 1/160) ( P = 4.2 × 10 -6 , OR = 0.23). A functional study demonstrated 20 that brucellosis patients carrying the protective allele (A) showed significantly lower expression 21 of the TNFAIP3 gene in their peripheral blood mononuclear cells and showed increased NF-κB 22 signaling. Monocytes from individuals carrying the A allele that were stimulated with B. abortus 23 had lower mRNA levels of TNFAIP3 and produced more IL-10, IL-6, and IL-1β than those from 24 TT allele carriers. These data showed that the autoimmune disease-associated risk variants, 25 TT>A, of the TNFAIP3 locus play a protective role in the pathogenesis of brucellosis. Our findings suggest that disruption of the normal function of the TNFAIP3 gene might serve as a 27 therapeutic target for the treatment of brucellosis. in which the TT>A variants are found binds to NF-κB transcription factors p50, p65, and and delivers them to the promoter region of the TNFAIP3 gene, activating transcription in multiple types of cells. The SLE-associated risk A allele disrupts the binding of NF-κB transcription factors and significantly reduces the expression of TNFAIP3 . In our published study, we also showed that TALEN-mediated TT>A-enhancer leads to reduced expression of TNFAIP3 and significant increases in NF-κB signaling activity These have positioned the TT>A variants as NF-κB signaling modifiers, and they might play a role in infectious diseases. As shown in this study, the SLE-associated risk allele was significantly associated with a decreased risk of brucellosis. cytokines The TT>A functional variants to reduced expression of TNFAIP3 and enhanced NF-κB predisposes individuals to autoimmune diseases while protecting them from brucellosis. We therefore assessed the role of TT>A variants in regulating the gene expression of multiple cytokines. Our data showed that increased activity of NF-κB in monocytes results in a