Possible use of miRNAs-146a and -499 expression and their polymorphisms as diagnostic markers for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disorder affecting the peripheral joints. Different microRNAs had been investigated in RA including miRNA-146a meanwhile, miRNA-499 there were no studies to prove its expression in RA serum samples. This study was performed to investigate expression of both miRNAs-146a and -499 and their polymorphisms in Egyptian patients with RA and to evaluate their relationship with clinico-pathological data. The present study includes 108 subjects classified into two main groups: 52 RA patients and 56 unrelated healthy controls. RA patients were subclassified according to DAS28 score into inactive (23 patients) and active (29 patients). Quantitative expression of serum miRNA-146a, miRNA-499 as well as their Genotyping rs2910164 (C/G) and rs3746444 (T/C), respectively, were done to all subjects using real-time PCR. Serum miRNA-146a and -499 were significantly over expressed in RA patients, but they were not correlated to disease activity. Serum miRNA-146a was negatively correlated with anti-nuclear antibodies (ANA). miRNA-146a (rs2910164) genotyping revealed that the GG genotype and the frequency of the G allele were significantly higher in RA patients compared to the controls. miRNA-499 (rs3746444), genotyping revealed that the CC genotype and the frequency of the C allele were significantly higher. It can be concluded that both miRNAs-146a and -499 can be used as diagnostic markers for RA patients. Both miRNA-146a (rs2710164) and miRNA-499 (rs3746444) were significantly associated with RA susceptibility. The C allele of miRNA-146a (rs2710164) can be considered to be protective. On the other hand, the C allele of miRNA-499 (rs3746444) was significantly associated with RA susceptibility.

Epigenetic Regulation Mediated by microRNAs in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

“…However, the reported genetic variants only explain <40% of the overall heritability of RA, leaving the majority of the heritability unaccounted for, thus suggesting the need for more studies that employ different approaches and populations in order to identify the missing causes. Association studies to miRNA loci provided the opportunity to identify RA-associated functional or causal variants within different populations, such as Chinese (Yang et al, 2011;Yang et al, 2012), Egyptian (El-Shal et al, 2013;Ayeldeen et al, 2018;), Polish (Bogunia-Kubik et al, 2016, Mexican (Aleman-Avila et al, 2017), and Iranian (Hashemi et al, 2013). The rs3746444 (20q11.22, A>G) polymorphism of miR-499, which is encoded by an intron of MYH7B, is significantly linked to RA risk, disease activity, and methotrexate (MTX) toxicity (Toraih et al, 2016); interestingly, the AA genotype shows higher disease activity and MTX toxicity than AG/GG genotypes (Fattah et al, 2018).…”

“…The rs3746444 (20q11.22, A>G) polymorphism of miR-499, which is encoded by an intron of MYH7B, is significantly linked to RA risk, disease activity, and methotrexate (MTX) toxicity (Toraih et al, 2016); interestingly, the AA genotype shows higher disease activity and MTX toxicity than AG/GG genotypes (Fattah et al, 2018). Gene expression and genetic polymorphisms of miR-146a and miR-499 showed diagnostic potential for RA (Ayeldeen et al, 2018).In addition, miR-146a rs2910164 is associated with RA susceptibility in the Egyptian population, in which the C allele is protective (Ayeldeen et al, 2018;Fattah et al, 2018). Consistently, the polymorphism rs3027898 in IRAK1, the target gene of miR-146a, is linked to RA in the Greek population (Chatzikyriakidou et al, 2010).…”

Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

“…In addition, gene expression and genetic polymorphisms of miR-146a and miR-499 showed diagnostic potentials for rheumatoid arthritis (23). rs2910164 in miR-146a was identified to be associated with RA susceptibility in the Egyptian population, in which C allele was protective (23,28). rs3027898 in IRAK1 which is the target gene of miR-146a was demonstrated associated RA in Greece population (29).…”

“…Majority of the heritability is still missing which require to be identified with more studies with different approaches and populations. Association study to miRNA locus provided an opportunity to identify RA associated functional or causal variants within different population Chinese (19,20), Egyptians (21)(22)(23), Polish (24), Mexican (25), and Iranians (26). rs3746444 (20q11.22, A>G) in miR-499 and intron of MYH7B was demonstrated to be significantly linked to RA risk, disease activity, and methotrexate toxicity (27) in which The AA genotype had higher disease activity and methotrexate toxicity compared with AG/GG genotypes (28).…”

“…rs3746444 (20q11.22, A>G) in miR-499 and intron of MYH7B was demonstrated to be significantly linked to RA risk, disease activity, and methotrexate toxicity (27) in which The AA genotype had higher disease activity and methotrexate toxicity compared with AG/GG genotypes (28). In addition, gene expression and genetic polymorphisms of miR-146a and miR-499 showed diagnostic potentials for rheumatoid arthritis (23). rs2910164 in miR-146a was identified to be associated with RA susceptibility in the Egyptian population, in which C allele was protective (23,28).…”