TNFAIP3 F127C Coding Variation in Greek Primary Sjogren's Syndrome Patients.

Adrianos Nezos,Clio P Mavragani,Eliona Gkioka,Michael Koutsilieris,Athanasios G Tzioufas,Michael Voulgarelis

doi:10.1155/2018/6923213

Abstract

Tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) gene encodes the A20 protein, an important negative feedback regulator of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. A coding TNFAIP3 variant, namely rs2230926, has been previously linked to B cell non-Hodgkin's lymphoma (NHL) development in patients with Sjogren's syndrome (SS) of French and UK origin. Herein, we aimed to determine the prevalence of rs2230926 in a Greek primary SS cohort and explore possible associations with disease characteristics. The rs2230926 gene variant was genotyped in 327 primary Greek SS patients (ninety-one complicated by NHL (SS-lymphoma)) and 448 Greek healthy controls (HC) of similar age and sex distribution. Clinical and laboratory characteristics were also recorded and gene expression of relevant genes of the NF-κB pathway was quantitated by real-time PCR in available whole peripheral blood (PB) from 165 primary SS patients. Increased prevalence of the rs2230926 mutant variant was detected in both SS-lymphoma and SS-nonlymphoma subgroups compared to HC (8.8% vs. 7.6% vs. 3.6%, p values: 0.04 and 0.03, respectively) in association with higher IgM, LDH serum levels, and PB Bcl-XL transcripts but lower leucocyte and neutrophil counts. Of interest, approximately one-fifth of SS-lymphoma cases with age at disease onset ≤ 40 years carried the rs2230926 variant (18.2% vs. 3.6%, OR 95% (CI): 6.0 (1.8–19.8), p value: 0.01). We postulate that deregulation of the NF-κB pathway as a result of the TNFAIP3 rs2230926 aberration increases SS and SS lymphoma susceptibility particularly in patients with early disease onset.

Highlights

Primary Sjogren’s syndrome (SS)—classically considered a chronic autoimmune exocrinopathy leading to oral and ocular dryness [1,2,3]—is characterized by the highest susceptibility for B cell non-Hodgkin’s lymphoma (NHL) among all autoimmune diseases [1,2,3,4,5]
A growing body of evidence suggests that activation of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway is a critical step in the pathogenesis of both primary SS and B cell hematological malignancies including B cell NHL, the major type of primary SS-related lymphomas
The TNFAIP3 rs2230926 mutant variant emerged as a risk factor for both primary SS and SS-related lymphoma susceptibility

Summary

Introduction

Primary Sjogren’s syndrome (SS)—classically considered a chronic autoimmune exocrinopathy leading to oral and ocular dryness [1,2,3]—is characterized by the highest susceptibility for B cell non-Hodgkin’s lymphoma (NHL) among all autoimmune diseases [1,2,3,4,5]. A growing body of evidence suggests that activation of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway is a critical step in the pathogenesis of both primary SS and B cell hematological malignancies including B cell NHL, the major type of primary SS-related lymphomas. Recent studies revealed that B cell-activating factor-receptor (BAFF-R) His159Tyr mutation and a tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) germline coding variation—both associated with the activation of the NF-κB pathway—are important contributors in primary SS and SS-related lymphomagenesis [11,12,13,14,15,16]. The TNFAIP3 gene encodes the A20 protein essential for the development and functional performance of dendritic, B and T cells and macrophages as well as an important negative feedback regulator of the NF-κB pathway [17]. A20-deficient mice die early due to multiorgan inflammation and cachexia as a result of excessive TNF-induced

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