Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

Katarzyna Bogunia-Kubik,Marzena Ciechomska,Milena Iwaszko,Jerzy Świerkot,Barbara Wysoczańska,Dagmara Piątek

doi:10.1007/s00005-016-0443-5

Abstract

MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA). Through NF-κB pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17. It has been also suggested that single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA development. These observations prompted us to analyze the potential associations between the miR-146a-3p (rs2910164, G > C) and NFkB1 (rs28362491, ins/del ATTG) polymorphisms and miR-146a-5p expression in patients’ sera in relation to clinical outcome of the treatment as well as predisposition to RA. Genotyping was performed in 111 patients and 130 healthy individuals while 16 controls and 13 RA patients (before and after three months of therapy with TNF-α inhibitors (TNFi)) were studied for the circulating miR-146a-5p serum expression level. Patients carrying the NFkB1 ins/ins genotype were characterized by worse response to TNFi treatment (p = 0.023). In patients, before TNFi therapy, expression levels of miR-146a-5p were less (0.422 ± 0.171) as compared to those detected after three months of treatment (1.809 ± 0.658, p = 0.033) and observed for healthy controls (5.302 ± 2.112, p = 0.048). Moreover, patients with higher circulating miR-146a-5p levels after three months of TNFi administration were more frequently carrying the rs2910164-C allele (p = 0.032). These results support the hypothesis that miR-146a might be involved in pathogenesis of RA and imply that miR-146a-3p polymorphism may be associated with miR-146a-5p levels in serum after anti-TNF-α treatment.

Highlights

Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disease primarily characterized by chronic synovitis and progressive joint destruction
We found no evidence that genotype frequencies of the two polymorphisms examined were different from those expected from Hardy– Weinberg equilibrium (HWE) both in controls and cases
Neither the rs2910164 miR-146a-3p nor the rs28362491 NFkB1 polymorphism was found to be associated with predisposition to rheumatoid arthritis (RA)

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disease primarily characterized by chronic synovitis and progressive joint destruction. The exact cause of RA remains unknown, it has been shown that both genetic and environmental factors play a role in the disease development (McInnes and Schett 2011). Anti-tumor necrosis factor (anti-TNF) biologic agents represent a novel approach in RA management that significantly improved the prognosis of RA patients. Substantial proportion of patients do not respond to the therapy with TNF inhibitors. The reasons of anti-TNF therapy failure have not been established to date. The search of biomarkers of anti-TNF agents’ efficacy is of importance to optimize patient benefit and reduce cost of treatment

Objectives

Methods

Results

Conclusion