Functional polymorphisms in pre-miR146a and pre-miR499 are associated with systemic lupus erythematosus but not with rheumatoid arthritis or Graves’ disease in Mexican patients

Abstract

Recently, different microRNA (miRNA) gene polymorphisms have been evaluated in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves’ disease (GD). In the present study, we examined three single-nucleotide polymorphisms (SNPs) located in the pre-miR-146a (rs2910164G/C), pre-miR-196a-2 (rs11614913C/T), and pre-miR-499 (rs3746444A/G) genes. Our study population included 900 Mexican patients with RA, SLE, or GD, as well as 486 healthy control individuals with no family history of inflammatory or autoimmune diseases. Genotyping was performed using TaqMan probes and a 5′ exonuclease assay. None of the investigated SNPs were associated with RA or GD susceptibility under any genetic model (co-dominant, recessive, or dominant). Genotype and allele frequencies of the miR-196a-2 rs11614913C/T polymorphism were similar between SLE cases and controls. In contrast, the miR-146a rs2910164G/C and miR-499 rs3746444A/G polymorphisms were associated with SLE susceptibility. These SNPs were not associated with lupus nephritis (LN). Our results suggest that polymorphisms in miR-146a, miR-196a-2, and miR-499 are not associated with RA or GD susceptibility. This is the first report documenting that the miR-146a rs2910164G/C and miR-499 rs3746444 polymorphisms are associated with SLE susceptibility but not with LN.

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

“…Consistently, the polymorphism rs3027898 in IRAK1, the target gene of miR-146a, is linked to RA in the Greek population (Chatzikyriakidou et al, 2010). However, follow-up studies showed inconsistent results in Polish (Bogunia-Kubik et al, 2016), Mexican (Aleman-Avila et al, 2017), and Chinese (Yang et al, 2011;Yang et al, 2012;Zhou et al, 2015b;Yang et al, 2017) populations. SNPs in other miRNAs were also tested in some studies, but their association with RA in other populations was not significant.…”

“…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).…”

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

“…SNPs located in other miRNAs were also tested in some studies however the association is not quite significant. For example, miR-196a-2 (rs11614913C/T) and miR-499 (rs3746444A/G) were showed do not have significant association with RA in Mexico population (25). miR-146a (rs2910164) (20,31) and miR-499 (rs3746444) (20,30) were found do not have significant association with RA in Chinese.…”

“…rs3027898 in IRAK1 which is the target gene of miR-146a was demonstrated associated RA in Greece population (29). However, follow-up studies showed inconsistent result in Poland (24), Mexico (25) and China (19,20,30,31) population. SNPs located in other miRNAs were also tested in some studies however the association is not quite significant.…”

“…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).…”