Inflammatory arthritis is a group of complex diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), etc. And it is characterized by inflammatory cell infiltration into the joints [
MicroRNAs (miRNAs) are small noncoding RNAs, which are about 22 nucleotides long. They play an important role in regulating transcription and translation [
MiRNA-146 is located on human chromosome 5q34 and related to immune regulation, inflammatory signaling pathway, because it can regulate the expression of IL-1 receptor-associated kinase (IRAK1) and IRAK2 and targets TNF receptor-associated factor 6 (TRAF6) [
Considering the results of miRNA-146 and miRNA-499 polymorphisms with inflammatory arthritis are inconsistent [
A systematic search of studies on the association of miRNA-146 and miRNA-499 polymorphisms with inflammatory arthritis susceptibility was conducted in PubMed, Web of science, Elsevier ScienceDirect, and Cochrane Library. Keywords for the search were as follows: (“microRNA” or “miRNA” or “microRNAs”) and (“Inflammatory arthritis”) and (“polymorphism” or “variant” or “genotype” or “SNP” or “mutations”). All relevant studies were retrieved. We screened those studies by reading its titles, abstracts, and contents carefully.
The inclusion criteria were (i) studies involving the association between miRNA gene polymorphisms and inflammatory arthritis; (ii) case-control study; (iii) studies based on human; (iv) studies providing the detailed relevant genotype data of both case group and control group. Studies were excluded if (i) the study was a review, editorial, abstract, case report, or unpublished article; (ii) studies were nonhuman studies or animal experiments or cell experiments; (iii) studies had no controls or no detailed relevant genotype data.
The data of the eligible studies were extracted by one investigator (Mr.Wang). The following information were collected: first author’s name; year of publication; type of disease; country; region; genotyping methods; number of cases and controls in each study; characteristics of controls; category of polymorphisms and other additional information.
The included studies in this meta-analysis were evaluated by another inspector (Pan). The quality assessment was based on the modified Newcastle-Ottawa Quality Assessment Scale (NOS). The scale consists of eight multiple-choice questions that involve subjects' selection, comparability in cases and controls, and assessment of exposure. High-quality response earns a point, totaling up to nine points (the comparability question earns up to two points). The higher score indicates better quality.
All statistical analyses were performed by Stata 12.0 (StataCorp, College Station, TX, USA) software. OR and 95% CI were used to evaluate the strength of association between miRNA-146/499 polymorphisms with inflammatory arthritis susceptibility under different genetic models. The effect of heterogeneity was evaluated using
A total of 390 studies were retrieved from PubMed, Web of science, Elsevier Science Direct and Cochrane Library. Finally, 18 eligible studies were included in this meta-analysis. A flowchart of the included and excluded studies was shown in Figure
A flowchart of the included and excluded studies.
Table
The main features of included studies.
Author | Year | Disease | Country | Region | Genotyping methods | Number of Cases | Number of controls | Characteristics of controls | Polymorphisms | NOS score |
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Chatzikyriakidou A | 2010 | RA | Greece | Europe | PCR–RFLP | 136 | 147 | Healthy | rs2910164(miRNA-146) | 6 |
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Yang XK | 2016 | RA | China | Asia | TaqMan | 386 | 576 | Healthy | rs3746444(miRNA-499) | 7 |
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Singh S | 2014 | JIA-ERA | India | Asia | PCR–RFLP | 150 | 216 | Healthy | rs2910164(miRNA-146) | 7 |
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El-Shal AS | 2013 | RA | Egypt | Middle East | PCR–RFLP | 217 | 245 | Healthy | rs2910164(miRNA-146), | 6 |
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Shaker OG | 2018 | RA | Egypt | Middle East | TaqMan | 104 | 112 | Healthy | rs2910164(miRNA-146), | 7 |
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Hashemi M | 2012 | RA | Iran | Middle East | T-ARMS-PCR | 104 | 110 | Healthy | rs2910164(miRNA-146), | 6 |
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Yang B | 2010 | RA | China | Asia | PCR–RFLP | 208 | 240 | Healthy | rs2910164(miRNA-146), | 7 |
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Aleman-Avila I | 2017 | RA | Mexico | North America | TaqMan | 412 | 486 | Healthy | rs2910164(miRNA-146), | 7 |
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Zhou X | 2015 | RA | China | Asia | NA | 598 | 821 | NA | rs2910164(miRNA-146) | 5 |
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Hassine HB | 2017 | RA | Tunisia | Middle East | PCR–RFLP | 165 | 150 | Healthy | rs2910164(miRNA-146) | 6 |
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Maharaj AB(1) | 2018 | PsA | South Africa | Africa | PCR–RFLP | 84 | 62 | Healthy | rs2910164(miRNA-146) | 6 |
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Maharaj AB(2) | 2018 | PsA | South Africa | Africa | PCR–RFLP | 32 | 38 | Healthy | rs2910164(miRNA-146) | 6 |
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Jimenez-Morales S | 2012 | JRA | Mexico | North America | TaqMan | 210 | 531 | Healthy | rs2910164(miRNA-146) | 7 |
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Ciccacci C | 2016 | RA | Italy | Europe | TaqMan | 192 | 298 | Healthy | rs2910164(miRNA-146) | 7 |
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Ayeldeen G | 2018 | RA | Egypt | Middle East | real-time PCR | 52 | 56 | Healthy | rs2910164(miRNA-146), | 6 |
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Toraih EA | 2016 | RA | Egypt | Middle East | TaqMan | 95 | 200 | Healthy | rs3746444(miRNA-499), | 6 |
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Fattah SA | 2018 | RA | Egypt | Middle East | PCR–RFLP | 100 | 100 | Healthy | rs3746444(miRNA-499) | 6 |
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Bogunia-Kubik K | 2016 | RA | Poland | Europe | PCR–RFLP | 111 | 130 | Healthy | rs2910164(miRNA-146) | 6 |
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Chatzikyriakidou A | 2010 | PsA | Greece | Europe | PCR–RFLP | 29 | 66 | NA | rs2910164(miRNA-146) | 6 |
HWE: Hardy–Weinberg equilibrium; NOS: Newcastle-Ottawa Quality Assessment Scale.
Meta-analysis indicated that there is lack of association between miRNA-146 rs2910164 polymorphism and inflammatory arthritis susceptibility in the overall population (G vs C, OR: 1.061, 95% CI= 0.933-1.207,
The forest plot about association between miRNA-146 rs2910164 and inflammatory arthritis under allelic model (G vs C).
Meta-analysis indicated significant association between miRNA-499 rs3746444 polymorphism and inflammatory arthritis susceptibility in the overall population (C vs T, OR: 1.422, 95% CI= 1.159-1.745,
The forest plot about association between miRNA-499 rs3746444 and inflammatory arthritis under allelic model (C vs T).
The results of heterogeneity test were shown in Table
The results of meta-analysis, heterogeneity test, and publication bias.
polymorphism | Number of studies | Comparable genotype | No. of Cases/Controls | Test of association | Test of heterogeneity | Test of publication bias | Model | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Begg’s test | Egger’s test | ||||||||||||
OR (95%CI) | | | | Z | | t | | ||||||
rs2910164 | |||||||||||||
Overall | 16 | G vs C | 2802/3708 | 1.061(0.933-1.207) | 0.365 | 58.80% | 0.002 | 0.14 | 0.893 | 0.60 | 0.559 | R | |
Region | |||||||||||||
Europe | 4 | G vs C | 468/641 | 1.017(0..836-1.236) | 0.868 | 0.00% | 0.753 | 1.02 | 0.308 | -2.93 | 0.100 | F | |
Asia | 3 | G vs C | 956/1277 | 0.991(0.877-1.120) | 0.890 | 0.00% | 0.412 | 1.04 | 0.296 | -1.89 | 0.309 | F | |
Middle East | 5 | G vs C | 642/673 | 1.449(1.229-1.709) | 0.001 | 47.30% | 0.108 | 0.24 | 0.806 | 0.53 | 0.630 | F | |
Africa | 2 | G vs C | 116/100 | 0.615(0.405-0.935) | 0.023 | 0.50% | 0.316 | 0.00 | 1.000 | NA | NA | F | |
North America | 2 | G vs C | 620/1017 | 0.955(0.820-1.111) | 0.551 | 36.40% | 0.210 | 0.00 | 1.000 | NA | NA | F | |
HWE | |||||||||||||
Y | 13 | G vs C | 2524/3359 | 1.053(0.916-1.211) | 0.469 | 61.90% | 0.002 | 0.18 | 0.855 | 0.99 | 0.344 | R | |
Overall | 16 | GC+CC | 2802/3708 | 0.919(0.762-1.110) | 0.381 | 57.20% | 0.002 | -0.05 | 1.000 | 0.05 | 0.963 | R | |
Region | |||||||||||||
Europe | 4 | GC+CC | 468/641 | 1.000(0.784-1.276) | 0.998 | 0.00% | 0.606 | 1.70 | 0.089 | 13.66 | 0.005 | F | |
Asia | 3 | GC+CC | 956/1277 | 0.980(0.795-1.209) | 0.851 | 0.00% | 0.869 | 0.00 | 1.000 | 0.16 | 0.896 | F | |
Middle East | 5 | GC+CC vs GG | 642/673 | 0.530(0.320-0.877) | 0.014 | 64.30% | 0.024 | 0.73 | 0.462 | -0.99 | 0.394 | R | |
Africa | 2 | GC+CC vs GG | 116/100 | 1.915(1.107-3.314) | 0.020 | 49.40% | 0.160 | 0.00 | 1.000 | NA | NA | F | |
North America | 2 | GC+CC vs GG | 620/1017 | 1.009(0.735-1.385) | 0.956 | 57.20% | 0.127 | 0.00 | 1.000 | NA | NA | R | |
HWE | |||||||||||||
Y | 13 | GC+CC vs GG | 2524/3359 | 0.942(0.780-1.137) | 0.532 | 55.80% | 0.007 | 0.06 | 0.951 | 0.02 | 0.982 | R | |
Overall | 16 | CC vs GG+GC | 2802/3708 | 0.935(0.821-1.065) | 0.310 | 34.60% | 0.086 | 1.22 | 0.224 | 0.98 | 0.343 | F | |
Region | |||||||||||||
Europe | 4 | CC vs GG+GC | 468/641 | 0.914(0.581-1.439) | 0.699 | 0.00% | 0.839 | -0.34 | 1.000 | 0.23 | 0.837 | F | |
Asia | 3 | CC vs GG+GC | 956/1277 | 1.149(0.803-1.645) | 0.447 | 59.10% | 0.087 | 1.04 | 0.296 | 2.69 | 0.227 | R | |
Middle East | 5 | CC vs GG+GC | 642/673 | 0.631(0.483-0.823) | 0.001 | 0.00% | 0.431 | 0.24 | 0.806 | -0.60 | 0.590 | F | |
Africa | 2 | CC vs GG+GC | 116/100 | 2.211(0.674-7.256) | 0.191 | 0.00% | 0.581 | 0.00 | 1.000 | NA | NA | F | |
North America | 2 | CC vs GG+GC | 620/1017 | 1.151(0.837-1.582) | 0.387 | 0.00% | 0.739 | 0.00 | 1.000 | NA | NA | F | |
HWE | |||||||||||||
Y | 13 | CC vs GG+GC | 2524/3359 | 0.959(0.834-1.103) | 0.556 | 40.20% | 0.066 | 0.55 | 0.583 | 0.37 | 0.722 | F | |
rs3746444 | |||||||||||||
Overall | 9 | C vs T | 1678/2125 | 1.422(1.159-1.745) | 0.001 | 63.30% | 0.005 | 1.15 | 0.251 | 1.30 | 0.234 | R | |
Region | |||||||||||||
Asia | 2 | C vs T | 594/816 | 1.128(0.904-1.406) | 0.286 | 0.00% | 0.573 | 0.00 | 1.000 | NA | NA | F | |
Middle East | 6 | C vs T | 672/823 | 1.614(1.219-2.137) | 0.001 | 66.80% | 0.010 | 0.75 | 0.452 | 0.77 | 0.485 | R | |
North America | 1 | C vs T | 412/486 | 1.215(0.845-1.748) | 0.294 | NA | NA | NA | NA | NA | NA | F | |
HWE | |||||||||||||
Y | 7 | C vs T | 1479/1815 | 1.390(1.214-1.591) | 0.001 | 31.00% | 0.191 | 0.30 | 0.764 | 0.99 | 0.368 | F | |
Overall | 9 | TC+CC vs TT | 1678/2125 | 1.409(1.072-1.852) | 0.014 | 67.50% | 0.002 | 0.10 | 0.917 | 1.03 | 0.335 | R | |
Region | |||||||||||||
Asia | 2 | TC+CC vs TT | 594/816 | 1.138(0.891-1.454) | 0.301 | 0.00% | 0.374 | 0.00 | 1.000 | NA | NA | F | |
Middle East | 6 | TC+CC vs TT | 672/823 | 1.634(1.062-2.513) | 0.026 | 73.40% | 0.002 | 0.75 | 0.452 | 0.10 | 0.924 | R | |
North America | 1 | TC+CC vs TT | 412/486 | 1.188(0.809-1.742) | 0.379 | NA | NA | NA | NA | NA | NA | F | |
HWE | |||||||||||||
Y | 7 | TC+CC vs TT | 1479/1815 | 1.399(1.190-1.645) | 0.001 | 38.20% | 0.138 | 0.00 | 1.000 | 1.11 | 0.319 | F | |
Overall | 9 | CC vs TT+TC | 1678/2125 | 1.872(1.420-2.467) | 0.001 | 0.00% | 0.588 | 0.10 | 0.917 | 0.42 | 0.686 | F | |
Region | |||||||||||||
Asia | 2 | CC vs TT+TC | 594/816 | 1.224(0.551-2.717) | 0.619 | 0.00% | 0.495 | 0.00 | 1.000 | NA | NA | F | |
Middle East | 6 | CC vs TT+TC | 672/823 | 1.960(1.455-2.641) | 0.001 | 0.00% | 0.462 | 0.38 | 0.707 | 0.66 | 0.545 | F | |
North America | 1 | CC vs TT+TC | 412/486 | 3.557(0.369-34.331) | 0.273 | NA | NA | NA | NA | NA | NA | F | |
HWE | |||||||||||||
Y | 7 | CC vs TT+TC | 1479/1815 | 1.910(1.334-2.736) | 0.001 | 0.00% | 0.696 | 0.00 | 1.000 | -0.21 | 0.840 | F |
R: random-effects model; F: fixed-effects model; Y: yes (studies that suitable for HWE);
The plot of sensitivity analysis about association between miRNA-499 rs3746444 and inflammatory arthritis.
Both environmental factors and genetic factors are related to the development of inflammatory arthritis. As for miRNAs, it is reported that they are involved in cancers and autoimmune diseases [
Present meta-analysis included 18 relevant studies, 9 only about miRNA-146 rs2910164, 3 only about miRNA-499 rs3746444, and 6 about both miRNA-146 rs2910164 and miRNA-499 rs3746444. There were 5 studies not met Hardy–Weinberg equilibrium; we did not exclude those 5 studies. We conducted subgroup analysis according to HWE and found that the results are similar (Table
Of course, there were some limitations in this meta-analysis. First, we searched literature based on English; it may cause language bias. Second, the number of included studies was not sufficient, which could not conduct comprehensive analysis. Third, our data of meta-analysis were from retrospective research, which may be related to the methodological deficiencies. Finally, our meta-analysis did not take the interactions between environmental factors and genetic factors into account. Therefore, the results should be interpreted with caution.
In conclusion, the present study indicates that miRNA-499 rs3746444 polymorphism is associated with inflammatory arthritis susceptibility. However, there is lack of association between miRNA-146 rs2910164 polymorphism and inflammatory arthritis susceptibility. But, we find miRNA-146 rs2910164 and miRNA-499 rs3746444 polymorphism are associated with inflammatory arthritis in Middle East. Therefore, it is necessary to conduct more large-sample and more high-quality studies to further validate our findings.
All members declare they have no conflicts of interest.
This study was supported by grants from the Anhui Medical University Doctoral Research Foundation (XJ201414), Anhui Province Postdoctoral Foundation (2017B237), and the National Natural Science Foundation of China (11801010; 11526034).