BioMed Research International

BioMed Research International / 2019 / Article

Research Article | Open Access

Volume 2019 |Article ID 7305750 | https://doi.org/10.1155/2019/7305750

Dingjian Wang, Guixia Pan, "Association of rs2910164 Polymorphism in miRNA-146 and rs3746444 Polymorphism in miRNA-499 with Inflammatory Arthritis: A Meta-Analysis", BioMed Research International, vol. 2019, Article ID 7305750, 9 pages, 2019. https://doi.org/10.1155/2019/7305750

Association of rs2910164 Polymorphism in miRNA-146 and rs3746444 Polymorphism in miRNA-499 with Inflammatory Arthritis: A Meta-Analysis

Academic Editor: Salvatore Gallone
Received14 Mar 2019
Accepted23 Apr 2019
Published16 May 2019

Abstract

Objectives. The purpose of this study was to explore the association of miRNA-146 and miRNA-499 polymorphisms with inflammatory arthritis. Methods. 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. Eventually, 18 published studies were included. The strength of association between miRNA-146/499 polymorphisms and inflammatory arthritis susceptibility was assessed by odds ratios (ORs) with its 95% confidence intervals (CIs). Results. A total of 18 case-control studies, consisting of 3385 inflammatory arthritis patients and 4584 controls, were included in the meta-analysis. This meta-analysis showed significant association between miRNA-499 rs3746444 polymorphism and inflammatory arthritis susceptibility in overall population (C vs T, OR: 1.422, 95% CI= 1.159-1.745, P=0.001). Similar results were found in subgroup analysis by region. But we did not find association between miRNA-146 rs2910164 polymorphism and inflammatory arthritis susceptibility in overall population (C vs T, OR: 1.061, 95% CI= 0.933-1.207, P=0.365). Conclusions. 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 also find miRNA-146 rs2910164 and miRNA-499 rs3746444 polymorphism are associated with inflammatory arthritis in Middle East. Therefore, more large-scale studies are warranted to replicate our findings.

1. Introduction

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 [1, 2]. There is no doubt that environmental factors and genetic factors play an important role in the development of inflammatory arthritis.

MicroRNAs (miRNAs) are small noncoding RNAs, which are about 22 nucleotides long. They play an important role in regulating transcription and translation [36]. Some studies indicated that they also participate in cell proliferation, differentiation, and apoptosis [7, 8]. And, miRNAs can cause the degradation or translation repression of their target miRNA by binding to the 3′-untranslated region of specific mRNAs (messenger RNAs) [912]. Recently, some studies reported that miRNA may associate with inflammatory arthritis, such as miRNA-146 rs2910164 and miRNA-499 rs3746444. Therefore, we chose miRNA-146 rs2910164 and miRNA-499 rs3746444 to explore the association between its polymorphisms and inflammatory arthritis.

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) [13]. And, miRNA-499 is related to the expression of Interleukin-17 receptor B (IL-17RB), IL-2RB, IL-6, B and T lymphocyte attenuator (BTLA), and peptidyl arginine deiminase 4 (PADI4) [14]. Both miRNA-146 and miRNA-499 are thought to be involved in autoimmune and inflammatory diseases [15].

Considering the results of miRNA-146 and miRNA-499 polymorphisms with inflammatory arthritis are inconsistent [1620], this discrepancy might be caused by some studies that have small sample size, low statistical power, ethnicity differences, and publication bias. It is necessary to conduct meta-analysis to explore this association.

2. Methods

2.1. Search Strategy

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.

2.2. Eligibility Criteria

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.

2.3. Data Extraction

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.

2.4. Quality Assessment

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.

2.5. Statistical Analysis

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 statistics. Heterogeneity was recognized as statistically significant when %. According to the value of , we chose fixed-effects or random-effects model. All subgroups were analyzed. Sensitivity analysis was used to evaluate the influence of individual study on the overall OR. Publication bias was assessed by Funnel’s plot, Begg’s test and Egger’s test. An asymmetric plot and the value of Egger’s test or Begg’s test less than 0.05 were considered as significant publication bias.

3. Results

3.1. Literature Search

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 1.

3.2. Characteristics of the Included Studies

Table 1 showed the main features of those included studies. Those studies were all English articles, which have been published from 2010 to 2018. All studies included in this meta-analysis were case-control studies. Eighteen studies involving 3385 inflammatory arthritis patients and 4584 controls were included in this meta-analysis.


AuthorYearDiseaseCountryRegionGenotyping methodsNumber of CasesNumber of controlsCharacteristics of controlsPolymorphismsNOS score

Chatzikyriakidou A2010RAGreeceEuropePCR–RFLP136147Healthyrs2910164(miRNA-146)6

Yang XK2016RAChinaAsiaTaqMan386576Healthyrs3746444(miRNA-499)7

Singh S2014JIA-ERAIndiaAsiaPCR–RFLP150216Healthyrs2910164(miRNA-146)7

El-Shal AS2013RAEgyptMiddle EastPCR–RFLP217245Healthyrs2910164(miRNA-146),
rs3746444(miRNA-499)
6

Shaker OG2018RAEgyptMiddle EastTaqMan104112Healthyrs2910164(miRNA-146),
rs3746444(miRNA-499)
7

Hashemi M2012RAIranMiddle EastT-ARMS-PCR104110Healthyrs2910164(miRNA-146),
rs3746444(miRNA-499)
6

Yang B2010RAChinaAsiaPCR–RFLP208240Healthyrs2910164(miRNA-146),
rs3746444(miRNA-499)
7

Aleman-Avila I2017RAMexicoNorth AmericaTaqMan412486Healthyrs2910164(miRNA-146),
rs3746444(miRNA-499),
rs11614913(miRNA-196)
7

Zhou X2015RAChinaAsiaNA598821NArs2910164(miRNA-146)5

Hassine HB2017RATunisiaMiddle EastPCR–RFLP165150Healthyrs2910164(miRNA-146)6

Maharaj AB(1)2018PsASouth AfricaAfricaPCR–RFLP8462Healthyrs2910164(miRNA-146)6

Maharaj AB(2)2018PsASouth AfricaAfricaPCR–RFLP3238Healthyrs2910164(miRNA-146)6

Jimenez-Morales S2012JRAMexicoNorth AmericaTaqMan210531Healthyrs2910164(miRNA-146)7

Ciccacci C2016RAItalyEuropeTaqMan192298Healthyrs2910164(miRNA-146)7

Ayeldeen G2018RAEgyptMiddle Eastreal-time PCR5256Healthyrs2910164(miRNA-146),
rs3746444(miRNA-499)
6

Toraih EA2016RAEgyptMiddle EastTaqMan95200Healthyrs3746444(miRNA-499),
rs11614913(miRNA-196)
6

Fattah SA2018RAEgyptMiddle EastPCR–RFLP100100Healthyrs3746444(miRNA-499)6

Bogunia-Kubik K2016RAPolandEuropePCR–RFLP111130Healthyrs2910164(miRNA-146)6

Chatzikyriakidou A2010PsAGreeceEuropePCR–RFLP2966NArs2910164(miRNA-146)6

HWE: Hardy–Weinberg equilibrium; NOS: Newcastle-Ottawa Quality Assessment Scale.
3.3. Meta-Analysis of Association between miRNA-146 rs2910164 Polymorphism and Inflammatory Arthritis

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, P=0.365; GC+CC vs GG, OR: 0.919, 95% CI=0.762-1.110, P=0.381; CC vs GG+GC, OR: 0.935, 95% CI=0.821-1.065, P=0.310). After stratifying by region, it only showed the association between miRNA-146 rs2910164 polymorphism and inflammatory arthritis susceptibility in Middle East (Figure 2). This may be due to the differences in geographic region, ethnicity, and sample size.

3.4. Meta-Analysis of Association between miRNA-499 rs3746444 Polymorphism and Inflammatory Arthritis

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, P=0.001; TC +CC vs TT, OR: 1.409, 95% CI=1.072-1.852, P=0.014; CC vs TT+TC, OR: 1.872, 95% CI=1.420-2.467, P<0.001). After stratifying by region, the association between miRNA-499 rs3746444 polymorphism and inflammatory arthritis susceptibility was still extant in Middle East (Figure 3). But, we did not find this association in Asia and North America.

3.5. Heterogeneity and Publication Bias

The results of heterogeneity test were shown in Table 2. And the results of Begg’s test and Egger’s test were also shown in Table 2. As for some studies that had heterogeneity (%), the random-effects models were performed; others were analyzed by fixed-effects model. As for miRNA-499 rs3746444 polymorphism, the plot of sensitivity analysis was shown in Figure 4. And there was no significant evidence of publication bias found in the meta-analysis.


polymorphismNumber of studiesComparable genotypeNo. of Cases/Controls Test of association Test of heterogeneityTest of publication biasModel
Begg’s test Egger’s test
OR (95%CI)PI2PHZPtP

rs2910164
(miRNA-146)
Overall16G vs C2802/37081.061(0.933-1.207)0.36558.80%0.0020.140.8930.600.559R
Region
Europe4G vs C468/6411.017(0..836-1.236)0.8680.00%0.7531.020.308-2.930.100F
Asia3G vs C956/12770.991(0.877-1.120)0.8900.00%0.4121.040.296-1.890.309F
Middle East5G vs C642/6731.449(1.229-1.709)0.00147.30%0.1080.240.8060.530.630F
Africa2G vs C116/1000.615(0.405-0.935)0.0230.50%0.3160.001.000NANAF
North America2G vs C620/10170.955(0.820-1.111)0.55136.40%0.2100.001.000NANAF
HWE
Y13G vs C2524/33591.053(0.916-1.211)0.46961.90%0.0020.180.8550.990.344R
Overall16GC+CC
vs GG
2802/37080.919(0.762-1.110)0.38157.20%0.002-0.051.0000.050.963R
Region
Europe4GC+CC
vs GG
468/6411.000(0.784-1.276)0.9980.00%0.6061.700.08913.660.005F
Asia3GC+CC
vs GG
956/12770.980(0.795-1.209)0.8510.00%0.8690.001.0000.160.896F
Middle East5GC+CC vs GG642/6730.530(0.320-0.877)0.01464.30%0.0240.730.462-0.990.394R
Africa2GC+CC vs GG116/1001.915(1.107-3.314)0.02049.40%0.1600.001.000NANAF
North America2GC+CC vs GG620/10171.009(0.735-1.385)0.95657.20%0.1270.001.000NANAR
HWE
Y13GC+CC vs GG2524/33590.942(0.780-1.137)0.53255.80%0.0070.060.9510.020.982R
Overall16CC vs GG+GC2802/37080.935(0.821-1.065)0.31034.60%0.0861.220.2240.980.343F
Region
Europe4CC vs GG+GC468/6410.914(0.581-1.439)0.6990.00%0.839-0.341.0000.230.837F
Asia3CC vs GG+GC956/12771.149(0.803-1.645)0.44759.10%0.0871.040.2962.690.227R
Middle East5CC vs GG+GC642/6730.631(0.483-0.823)0.0010.00%0.4310.240.806-0.600.590F
Africa2CC vs GG+GC116/1002.211(0.674-7.256)0.1910.00%0.5810.001.000NANAF
North America2CC vs GG+GC620/10171.151(0.837-1.582)0.3870.00%0.7390.001.000NANAF
HWE
Y13CC vs GG+GC2524/33590.959(0.834-1.103)0.55640.20%0.0660.550.5830.370.722F
rs3746444
(miRNA-499)
Overall9C vs T1678/21251.422(1.159-1.745)0.00163.30%0.0051.150.2511.300.234R
Region
Asia2C vs T594/8161.128(0.904-1.406)0.2860.00%0.5730.001.000NANAF
Middle East6C vs T672/8231.614(1.219-2.137)0.00166.80%0.0100.750.4520.770.485R
North America1C vs T412/4861.215(0.845-1.748)0.294NANANANANANAF
HWE
Y7C vs T1479/18151.390(1.214-1.591)0.00131.00%0.1910.300.7640.990.368F
Overall9TC+CC vs TT1678/21251.409(1.072-1.852)0.01467.50%0.0020.100.9171.030.335R
Region
Asia2TC+CC vs TT594/8161.138(0.891-1.454)0.3010.00%0.3740.001.000NANAF
Middle East6TC+CC vs TT672/8231.634(1.062-2.513)0.02673.40%0.0020.750.4520.100.924R
North America1TC+CC vs TT412/4861.188(0.809-1.742)0.379NANANANANANAF
HWE
Y7TC+CC vs TT1479/18151.399(1.190-1.645)0.00138.20%0.1380.001.0001.110.319F
Overall9CC vs TT+TC1678/21251.872(1.420-2.467)0.0010.00%0.5880.100.9170.420.686F
Region
Asia2CC vs TT+TC594/8161.224(0.551-2.717)0.6190.00%0.4950.001.000NANAF
Middle East6CC vs TT+TC672/8231.960(1.455-2.641)0.0010.00%0.4620.380.7070.660.545F
North America1CC vs TT+TC412/4863.557(0.369-34.331)0.273NANANANANANAF
HWE
Y7CC vs TT+TC1479/18151.910(1.334-2.736)0.0010.00%0.6960.001.000-0.210.840F

R: random-effects model; F: fixed-effects model; Y: yes (studies that suitable for HWE); : the value of in the heterogeneity test.

4. Discussion

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 [15, 21]. But some recent studies about miRNA-146/499 polymorphisms and inflammatory arthritis are inconsistent; it needs us to explore the real association between miRNA-146/499 polymorphisms and inflammatory arthritis by conducting this meta-analysis.

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 2).

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.

Conflicts of Interest

All members declare they have no conflicts of interest.

Acknowledgments

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).

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Copyright © 2019 Dingjian Wang and Guixia Pan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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