Characteristics of A20 gene polymorphisms and clinical significance in patients with rheumatoid arthritis.

Lihua Zhu,Lingling Zhou,Bo Li,Jie Ren,Zhaoxia Li,Yangqiu Li,Liang Wang,Ling Xu,Yi Zhou,Lijian Yang,Huixia Wu,Xiuli Wu,Shaohua Chen,Xu Wang,Ziwei Liao

doi:10.1186/s12967-015-0566-1

Abstract

BackgroundThere are a number of studies regarding to the susceptibility of A20 SNPs in rheumatoid arthritis (RA); however, a few of these studies have shown an association between polymorphisms in the A20 gene and RA risk in the Chinese population. The aim of this study was to investigate the characteristics of A20 gene polymorphisms, the association between polymorphisms and clinical significance in Chinese RA patients.MethodsPCR and sequencing were used to identify A20 gene polymorphisms in peripheral blood mononuclear cells (PBMCs) (50 cases), synovial fluid (11 cases) from RA patients and PBMCs from 30 healthy individuals. Quantitative Real-time PCR (qRT-PCR) was used to analyze the A20 mRNA expression in 38 RA patients and 40 healthy individuals. Pearson’s Chi square test and two independent-samples Wilcoxon tests were used for statistical analysis.ResultsEight single nucleotide polymorphisms (SNPs) (rs5029937, rs3799491, rs598493, rs2307859, rs146534657, rs2230926, rs661561, and rs582757) were identified in PBMCs of RA patients. One new mutation (14284 T > A) was identified in synovial fluid mononuclear cells from one RA case. rs146534657 was identified for the first time in two RA cases. Patients with rs146534657 (12411 A > G, Asn102Ser) AG genotype or rs2230926 (12486 T > G, Phe127Cys) TG genotype had poor outcome. Significantly lower A20 mRNA expression was found in PBMCs from RA patients compared with healthy individuals (p < 0.001). There was a higher A20 mRNA expression in RA patients with rs2230926 TG genotype and rs146534657 AG genotype (11.56 ± 7.39) than patients with rs2230926 TT genotype and rs146534657 AA genotype (5.63 ± 4.37) (p = 0.031).ConclusionSignificantly lower A20 expression was found in RA patients. The polymorphisms of A20 were characterized in RA patients. We detected rs146534657 for the first time and identified a new A20 mutation (14284 T > A). A20 rs2230926 TG genotype and rs146534657 AG genotype may be related to poor outcome in RA patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0566-1) contains supplementary material, which is available to authorized users.

Highlights

There are a number of studies regarding to the susceptibility of A20 single nucleotide polymorphisms (SNPs) in rheumatoid arthritis (RA); a few of these studies have shown an association between polymorphisms in the A20 gene and RA risk in the Chinese population
All RA patients were assessed for clinical disease activity by a trained rheumatologist using disease activity score 28 (DAS 28), and their erythrocyte sedimentation rate (ESR), C reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibody (CCP) were collected [16]
All of the parameters were abnormal, including the ESR: 69.61 ± 34.63 mm/h, CRP: 35.67 ± 28.68 mg/l, RF: 247.89 ± 377.42 IU/ml, DAS28: 7.50 ± 1.28, and anti-CCP antibody positivity was found for 29 patients, while anti-CCP antibody negativity was found for 16 patients, anti-CCP antibody was not detected in 5 patients

Summary

Introduction

There are a number of studies regarding to the susceptibility of A20 SNPs in rheumatoid arthritis (RA); a few of these studies have shown an association between polymorphisms in the A20 gene and RA risk in the Chinese population. A20 acts as a negative-feedback regulator of NF-κB activation in response to multiple stimuli, including TNF, IL-1, TLR (Toll-like receptor) and NLR [Nod (nucleotide-binding oligomerization domain)-like receptor] ligands [6, 7]. Genome-wide association studies have implicated the A20 locus in susceptibility to multiple autoimmune diseases in different cohorts, including RA, systemic lupus erythematosus (SLE), psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and coronary artery disease. Many A20 single nucleotide polymorphisms (SNPs) were found to be associated with the susceptibility to autoimmune disease [11,12,13]

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