3 years ago

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

Xianjun Liu, Shaofeng Wang, Wenjing Gao, Haijun Li, Yang Wang, Lixin Lou, Wanguo Bao, Zhengkun Tu, Kaiyu Zhang, Hongxiao Song
Naturally occurring functional variants (rs148314165 and rs200820567, collectively referred to as TT>A) reduce the expression of the tumor necrosis factor α-induced protein 3 (TNFAIP3) gene, a negative regulator of NF-κB signaling, and predispose individuals to autoimmune disease. In this analysis, we conducted a genetic association study of the TT>A variants in 1209 controls and in 150 patients with brucellosis, an infectious disease, and further assessed the role of the variants in brucellosis. Our data demonstrated that the TT>A variants were correlated with cases of brucellosis (P = 0.002, OR = 0.34) and with individuals who had a positive serum agglutination test (SAT > 1/160) (P = 4.2 × 10-6, OR = 0.23). A functional study demonstrated that brucellosis patients carrying the protective allele (A) showed significantly lower expression of the TNFAIP3 gene in their peripheral blood mononuclear cells and showed increased NF-κB signaling. Monocytes from individuals carrying the A allele that were stimulated with B. abortus had lower mRNA levels of TNFAIP3 and produced more IL-10, IL-6, and IL-1β than those from TT allele carriers. These data showed that the autoimmune disease-associated risk variants, 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 therapeutic target for the treatment of brucellosis.

Publisher URL: http://doi.org/10.1128/JCM.01363-17

DOI: 10.1128/JCM.01363-17

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