Abstract

ABSTRACTNaturally 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-κB 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 × 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-κB 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-1β 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.

Highlights

  • Occurring functional variants reduce the expression of the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene, a negative regulator of NF-␬B signaling, and predispose individuals to autoimmune disease

  • We investigated the TTϾA functional variants, 42 kbp downstream of the TNFAIP3 gene, in our cohort of 1,209 healthy controls and 150 brucellosis patients

  • This is the first evidence that systemic lupus erythematosus (SLE)-associated risk variants play a protective role in an infectious disease, namely, brucellosis

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Summary

Introduction

Occurring functional variants (rs148314165 and rs200820567, collectively referred to as TTϾA) reduce the expression of the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene, a negative regulator of NF-␬B signaling, and predispose individuals to autoimmune disease. In this analysis, we conducted a genetic association study of the TTϾA variants in 1,209 controls and 150 patients with brucellosis, an infectious disease, and further assessed the role of the variants in brucellosis. 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␤ than those from TT allele carriers These data showed that autoimmune disease-associated risk variants, TTϾA, of the TNFAIP3 locus play a protective role in the pathogenesis of brucellosis. Transcription activation-like effector nuclease (TALEN)-mediated knockout of the TTϾA enhancer in HEK293T cells enhanced the activity of NF-␬B signaling

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