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

作者：Lou, Lixin; Bao, Wanguo; Liu, Xianjun; Song, Hongxiao; Wang, Yang; Zhang, Kaiyu; Gao, Wenjing; Li, Haijun; Tu, Zhengkun^*; Wang, Shaofeng^*

来源：Journal of Clinical Microbiology, 2018, 56(4): e01363-17.

DOI：10.1128/JCM.01363-17

• brucellosis
• inflammation
• single nucleotide polymorphism
• TNFAIP3
• NF-kappa B

Naturally occurring functional variants (rs148314165 and rs200820567, collectively referred to as TT>A) reduce the expression of the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene, a negative regulator of NF-kappa B signaling, and predispose individuals to autoimmune disease. In this analysis, we conducted a genetic association study of the TT>A variants in 1,209 controls and 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; odds ratio [OR] = 0.34) and with individuals who had a positive serum agglutination test (SAT) result (titer of >1/160) (P = 4.2 x 10(-6); OR = 0.23). A functional study demonstrated that brucellosis patients carrying the protective allele (A) showed significantly lower expression levels of the TNFAIP3 gene in their peripheral blood mononuclear cells and showed increased NF-kappa B signaling. Monocytes from individuals carrying the A allele that were stimulated with Brucella abortus had lower mRNA levels of TNFAIP3 and produced more interleukin-10 (IL-10), IL-6, and IL-1 beta than those from TT allele carriers. These data showed that autoimmune disease-associated risk variants, TT>A, of the TNFAIP3 locus play a protective role in the pathogenesis of brucellosis. Our findings suggest that a disruption of the normal function of the TNFAIP3 gene might serve as a therapeutic target for the treatment of brucellosis.

• 出版日期2018-4
• 单位吉林大学