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TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of rheumatoid arthritis

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Oncotarget. 2016; 7:82933-82942. https://doi.org/10.18632/oncotarget.12638

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Ming-Jie Wang, Hao-Yu Yang, Hui Zhang, Xindie Zhou, Rui-Ping Liu _ and Yuan-Yuan Mi

Abstract

Ming-Jie Wang1,*, Hao-Yu Yang1,*, Hui Zhang1, Xindie Zhou1, Rui-Ping Liu1, Yuan-Yuan Mi2

1Department of Orthopedics, Affiliated Hospital of Nanjing Medical University, Changzhou Second People’s Hospital, Changzhou, China

2Department of Urology, The Third Affiliated Hospital of Nantong University, Wuxi, PR China

*These authors have contributed equally to this work

Correspondence to:

Rui-Ping Liu, email: liuruiping216@sina.com

Yuan-yuan Mi, email: myywxsy2016@sina.com

Keywords: TNFAIP3, rheumatoid arthritis, meta-analysis, single nucleotide polymorphism

Received: August 08, 2016    Accepted: September 23, 2016    Published: October 13, 2016

ABSTRACT

Accumulating evidences suggested that tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene rs10499194, rs13207033 polymorphisms may be associated with the risk of rheumatoid arthritis (RA). However, these studies yielded contradictory findings. To clarify convincing associations, we conducted a comprehensive meta-analysis by searching in PubMed, Embase, and the China Knowledge Resource Integrated Database. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. A total of 13 case-control studies for rs10499194 polymorphism and 6 studies for rs13207033 polymorphism were included. Our data indicated that TNFAIP3 gene rs10499194, rs13207033 polymorphisms were associated with the decreased risk of RA. Stratification analyses of ethnicity indicated rs10499194, rs13207033 polymorphisms decreased the risk of RA among Caucasian populations, but not among Asian populations. In conclusion, this meta-analysis indicates that TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of RA, especially among Caucasian populations.


TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of rheumatoid arthritis | Wang | Oncotarget

INTRODUCTION

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is characterized by chronic destructive inflammation in synovial joints. To date, the etiology of RA is poorly understood, but it is believed that complex genetic and environmental factors play important roles in the pathogenesis of RA [1]. Previous studies have suggested that genetic factors may be account for approximately 50–65% of the risk of RA [2]. Human leukocyte antigen (HLA) alleles are well recognized to be implicated in the pathogenesis of RA [3]. However, family studies indicated that HLA alleles contribute to about 30% of genetic susceptibility and that non-HLA loci are also related to RA [2, 4].

Tumor necrosis factor alpha inducible protein 3 (TNFAIP3), a deubiquitinating protein, is reported to play a pivotal role in T cell activation and inflammatory signaling [5]. It can deregulate NF-κB-dependent gene expression via deubiquitinating specific NF-κB signaling molecules [6]. Genome-wide association studies (GWASs) have identified TNFAIP3 gene as a common genetic risk factor for RA [78]. A host of studies [7, 921] investigated the associations between TNFAIP3 gene rs10499194, rs13207033 polymorphisms and RA susceptibility, but with conflicting findings. However, these studies were conflicting and inconclusive due to clinical heterogeneity, different ethnic populations, and small sample sizes. In order to precisely elucidate the genetic roles for TNFAIP3 gene polymorphisms (rs10499194, rs13207033) in the development of RA, we performed a comprehensive meta-analysis of identified studies to clarify the possible association between TNFAIP3 gene rs10499194, rs13207033 polymorphisms and RA risk.

RESULTS

Characteristics of the included studies

We yielded a total of 251 citations after initial search. 77 citations were removed because of duplicates, and 141 citations were excluded after screening the titles and abstracts. 33 citations were selected for further full text review. 19 citations were excluded due to the following reasons: 9 investigated other polymorphisms; 4 citations did not provide detailed genotyping data; 2 were about juvenile idiopathic arthritis; 3 were reviews; and 1 was not case-control study. We finally identified 14 eligible citations [7, 921] including 17 studies (23,918 cases and 33,486 controls) in this meta-analysis. Selection for eligible studies included in this meta-analysis was presented in Figure 1. 6 studies with 11,166 cases and 11,231 controls examined rs13207033 polymorphism; 13 studies including 15,341 cases and 24,535 controls investigated rs10499194 polymorphism. The characteristics of included studies are summarized in Table 1. The Newcastle-Ottawa Scale (NOS) scores of all included studies ranged from 5 to 7 stars, suggesting that these studies were of high methodological quality.

Selection for eligible publications included in this meta-analysis.

Figure 1: Selection for eligible publications included in this meta-analysis.

Table 1: Characteristics of included studies

Author and year

Country

Ethnicity

Case

Control

HWE

NOS

rs10499194

CC

CT

TT

CC

CT

TT

Hegab_2016

Egypt

Caucasian

319

71

3

344

52

2

0.982

6

Zhang_2014

China

Asian

1156

12

4

1215

63

2

0.218

6

Hughes_2010

USA

African-American

374

164

18

558

213

20

0.951

7

Shimane_2010

Japan

Asian

2944

450

17

2049

243

7

0.943

6

Han_2009

Korea

Asian

1199

113

2

936

66

1

0.883

5

Coenen_2009

Dutch

Caucasian

790

499

79

972

614

97

0.998

7

Stark_2009

Slovakia

Caucasian

281

200

37

149

116

37

0.058

6

Perdigones_2009

Spain

Caucasian

305

275

46

306

287

70

0.824

6

Raychaudhuri_2008

Mixed

Caucasian

1353

1522

428

4636

5929

1895

0.993

7

Plenge_2007

USA

Caucasian

229

145

23

195

167

36

0.977

6

Plenge_2007

Sweden

Caucasian

560

280

35

519

276

37

0.968

6

Plenge_2007

North America

Caucasian

317

190

28

496

426

91

0.973

6

Plenge_2007

North America

Caucasian

491

327

55

673

604

136

0.977

6

rs13207033

GG

GA

AA

GG

GA

AA

Zhang_2014

China

Asian

1040

232

8

1048

216

16

0.203

7

Han_2009

Korea

Asian

987

295

27

773

208

19

0.257

5

Maxwell_2012

UK

Caucasian

149

106

13

129

116

16

0.129

6

Orozco_2009

UK

Caucasian

2067

1403

224

1563

1237

229

0.464

7

Dieguez-Gonzalez_2009

Spain

Caucasian

825

684

142

800

676

143

0.991

6

Plant_2010

Mixed

Caucasian

1614

1148

202

2214

1555

273

0.999

6

HWE, Hardy–Weinberg equilibrium; NOS, Newcastle-Ottawa Scale

Meta-analysis of TNFAIP3 gene rs10499194, rs13207033 polymorphisms

In the overall analysis, we detected significant association (Table 2) between TNFAIP3 gene rs10499194, rs13207033 polymorphisms with decreased RA risk (rs10499194, TT vs. CT+CC: OR, 0.80; 95% CI, 0.74–0.88, P < 0.001, Figure 2; rs13207033, GA vs. GG: OR, 0.88; 95% CI, 0.79–0.99, P = 0.034, Figure 3). Stratification analyses were conducted according to ethnicity (Table 3). Our data indicated that rs10499194 polymorphism was also significantly associated with a decreased risk of RA among Caucasian populations (TT vs. CT+CC: OR, 0.79; 95% CI, 0.72–0.86, P < 0.001, Figure 4), but not among Asian and African-American populations. We also found rs13207033 polymorphism was weakly associated with a decreased risk of RA among Caucasian populations (GA vs. GG: OR, 0.88; 95% CI, 0.79–1.00, P = 0.044). All included studies conform to Hardy–Weinberg equilibrium (HWE), indicating control subjects were representative of the general population.

Table 2: Meta-analysis of association between TNFAIP3 rs10499194, rs13207033 polymorphisms and RA risk

Comparison

OR(95%CI)

P-value

P for heterogeneity

I2 (%)

Model

rs10499194

T vs. C

0.91(0.81,1.02)

0.097

<0.001

85.0

Random

CT+TT vs. CC

0.90(0.78,1.03)

0.131

<0.001

84.9

Random

TT vs. CT+CC

0.80(0.74,0.88)

<0.001

0.115

33.4

Fixed

CT vs. CC

0.92(0.80,1.06)

0.239

<0.001

82.7

Random

TT vs. CC

0.75(0.62,0.90)

0.002

0.026

48.4

Random

rs13207033

A vs. G

0.96(0.89,1.04)

0.349

0.023

61.8

Random

GA+AA vs. GG

0.96(0.87,1.06)

0.446

0.025

61.1

Random

AA vs. GA+GG

0.90(0.81,1.01)

0.080

0.305

16.9

Fixed

GA vs. GG

0.88(0.79,0.99)

0.034

0.146

39.0

Fixed

AA vs. GG

0.97(0.89,1.07)

0.556

0.062

52.4

Random

*Bold values are statistically significant (P < 0.05).

Table 3: Summary of the subgroup analyses in this meta-analysis

Comparison

Category

Category

Studies

OR (95% CI)

P-value

rs10499194

T vs. C

Ethnicity

Asian

3

0.86(0.45,1.63)

0.638

Caucasian

9

0.86(0.78,0.94)

0.001

African–American

1

1.15(0.94,1.41)

0.173

CT+TT vs. CC

Ethnicity

Asian

3

0.81(0.40,1.65)

0.561

Caucasian

9

0.85(0.76,0.95)

0.005

African–American

1

1.17(0.92,1.47)

0.200

TT vs. CT+CC

Ethnicity

Asian

3

1.72(0.82,3.62)

0.153

Caucasian

9

0.79(0.72,0.86)

<0.001

African–American

1

1.29(0.68,2.46)

0.440

CT vs. CC

Ethnicity

Asian

3

0.75(0.35,1.61)

0.467

Caucasian

9

0.88(0.80,0.98)

0.020

African–American

1

1.15(0.90,1.46)

0.262

TT vs. CC

Ethnicity

Asian

3

1.75(0.83,3.68)

0.141

Caucasian

9

0.69(0.58,0.82)

<0.001

African–American

1

1.34(0.70,2.57)

0.374

rs13207033

A vs. G

Ethnicity

Asian

2

1.05(0.92,1.19)

0.451

Caucasian

4

0.93(0.85,1.03)

0.170

GA+AA vs. GG

Ethnicity

Asian

2

1.08(0.94,1.24)

0.296

Caucasian

4

0.92(0.82,1.04)

0.174

AA vs. GA+GG

Ethnicity

Asian

2

0.83(0.52,1.34)

0.454

Caucasian

4

0.91(0.81,1.02)

0.105

GA vs. GG

Ethnicity

Asian

2

0.85(0.53,1.37)

0.505

Caucasian

4

0.88(0.79,1.00)

0.044

AA vs. GG

Ethnicity

Asian

2

1.10(0.95,1.27)

0.207

Caucasian

4

0.93(0.84,1.03)

0.187

*Bold values are statistically significant (P < 0.05)

Forest plot shows odds ratio for the associations between rs10499194 polymorphism and RA risk (TT vs. CT&#x002B;CC).

Figure 2: Forest plot shows odds ratio for the associations between rs10499194 polymorphism and RA risk (TT vs. CT+CC).

Forest plot shows odds ratio for the associations between rs13207033 polymorphism and RA risk (GA vs. GG).

Figure 3: Forest plot shows odds ratio for the associations between rs13207033 polymorphism and RA risk (GA vs. GG).

Stratification analyses of ethnicity between rs10499194 polymorphism and RA risk (TT vs. CT&#x002B;CC).

Figure 4: Stratification analyses of ethnicity between rs10499194 polymorphism and RA risk (TT vs. CT+CC).

We assessed sensitivity by omitting each study once at a time in every genetic model for rs10499194 and rs13207033 polymorphisms. The pooled ORs for the effects of these two single nucleotide polymorphisms (SNPs) (rs10499194, TT vs. CT+CC: Figure 5) on the risk for RA risk indicated that our data were stable and trustworthy. Both Egger’s and Begg’s tests (rs10499194: TT vs. CT+CC, Figure 6) were used to evaluated the publication bias of this meta-analysis. Our data revealed that there was no obvious publication bias for rs10499194 and rs13207033 polymorphisms (data not shown).

Sensitivity analyses between the rs10499194 polymorphism and RA risk (TT vs. CT&#x002B;CC).

Figure 5: Sensitivity analyses between the rs10499194 polymorphism and RA risk (TT vs. CT+CC).

Begg&#x2019;s tests between rs10499194 polymorphism and RA risk (TT vs. CT&#x002B;CC).

Figure 6: Begg’s tests between rs10499194 polymorphism and RA risk (TT vs. CT+CC).

DISCUSSION

In this current meta-analysis, we found that TNFAIP3 gene rs10499194, rs13207033 polymorphisms were associated with the decreased risk of RA. Stratification analyses of ethnicity indicated that rs10499194 and rs13207033 polymorphisms decreased the risk of RA among Caucasians, but not among Asians.

Studies have demonstrated that NF-κB-dependent gene expression is significantly associated with the development of RA [21]. TNFAIP3 is an inhibitor of the NF-κB signaling pathway and it is indispensable in the development of RA [22]. Defects in TNFAIP3 expression are associated with development of RA [23]. Matmati et al. indicated that TNFAIP3 deficiency in myeloid cells triggers erosive polyarthritis resembling RA [24]. They revealed a pivotal and cell-specific function for TNFAIP3 in the pathogenesis of RA [24]. Recently, a number of [7, 921] studies explored the associations between TNFAIP3 gene polymorphisms (rs10499194, rs13207033) and RA risk. However, these studies obtained inconsistent results. The limitations of these studies including clinical heterogeneity, different ethnic populations, inadequate statistical power, and small sample sizes may contribute to the disaccord. Therefore, to obtain reliable conclusions, it is indispensable to conduct a comprehensive meta-analysis to demonstrate the associations between TNFAIP3 gene rs10499194, rs13207033 polymorphisms and RA susceptibility. Our data indicated that TNFAIP3 gene rs10499194 and rs13207033 polymorphisms decreased the risk of RA.

Previously, Lee et al. also performed a meta-analysis to investigate TNFAIP3 gene rs10499194 polymorphism with RA susceptibility [25]. They indicated that rs10499194 polymorphism was not associated with RA susceptibility [25]. Stratification analyses of ethnicity in their meta-analysis [25] suggested that rs10499194 polymorphism was weakly associated with an increased risk of RA among Asian populations, while no association was observed among Caucasian populations. However, our meta-analysis found that rs10499194 polymorphism was significantly associated with a decreased risk of RA among Caucasian populations, but not among Asian populations, indicating that diversity inheritance of different ethnicities. The reasons why the decreased risk of RA among Asians is not obvious are still unclear. The clinical heterogeneity, different ethnicities and small sample sizes may explain it. We think previous meta-analysis [25] conducted by Lee et al. had several limitations. First, Lee et al. did not include two studies [7, 16] which actually conformed to the inclusion criteria. Second, they identified a Spanish study [10] by Dieguez-Gonzalez et al., but we did not find the genotype numbers of rs10499194 polymorphism. Three, previous research indicated that searching one or two databases was insufficient for meta-analysis of case-control studies [26]. Lee et al. conducted a literature search only in the database of MEDLINE, but omitting Embase and other databases. Consequently, the reliability of their conclusions should be interpreted with caution. Due to these above limitations of previous meta-analysis, we re-conducted this meta-analysis. We believe our meta-analysis has some strength over previous meta-analysis for the following reasons. One, we identified 13 studies [7, 9, 1113, 16, 1821], including 15,341 cases and 24,535 controls with regard to rs10499194 polymorphism and the sample size of this meta-analysis was large enough. Two, sensitivity analysis indicated that our data about rs10499194 polymorphism were trustworthy and robust. Three, the power analysis indicated that our study had a power of 99.9% to detect the effect of rs10499194 polymorphism on RA susceptibility, assuming an OR of 0.80.

Regarding TNFAIP3 gene rs13207033 polymorphism, six studies explored the association between this SNP and RA risk. A study from UK [15] found rs13207033 polymorphism was significantly associated with a decreased risk of RA, but the remaining five studies [10, 11, 14, 17, 21] did not replicate the association. Therefore, we conducted the meta-analysis to demonstrate this SNP with RA risk. To our knowledge, this is the first meta-analysis to address the association between this SNP and RA risk. A weak association was obtained about rs13207033 polymorphism in our study. Stratification analyses by ethnicity also found a weak association between rs13207033 polymorphism and Caucasian RA risk.

Several potential limitations should be addressed in this meta-analysis. First, due to limited data, we could not perform further stratification analyses of other potential factors, such as anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF). Second, our results were based on unadjusted estimates for confounding factors, which might have affected the final conclusions. Third, we could not assess potential gene-gene and gene-environment interactions because of the lack of relevant data. Fourth, the heterogeneity of this meta-analysis was high in some genetic models. Fifth, the conclusions about rs10499194 polymorphism among Asians should be interpreted with caution due to limited sample size.

In conclusion, this meta-analysis indicates that TNFAIP3 gene rs10499194, rs13207033 polymorphisms are associated with the decreased risk of RA, especially among Caucasians. Further studies are necessary to validate whether TNFAIP3 gene rs10499194, rs13207033 polymorphisms contribute to RA susceptibility in other ethnic groups.

MATERIALS AND METHODS

Literature search and criteria of inclusion

We systematically searched the PubMed, Embase, and China Knowledge Resource Integrated Database to identify studies through July 26, 2016. The following search terms were used: “tumor necrosis factor alpha inducible protein 3,” ‘‘TNFAIP3,’’ ‘‘A20,’’ ‘‘Rheumatoid Arthritis,’’ ‘‘RA,’’ ‘‘polymorphism,’’ ‘‘SNP’’ and ‘‘polymorphisms’’. No restrictions were placed on the search. Additional initially omitted studies (such as reference lists of identified studies) have been identified by hand screening. The identified studies conformed to the following criteria: (1) studies that evaluated the association between RA risk and TNFAIP3 gene rs10499194 or rs13207033 polymorphism, (2) studied on human beings, (3) study provided sufficient data to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), and P value, and (4) case-control study.

Data extraction and quality assessment

Relevant information was carefully extracted from all eligible studies. The extracted information from all eligible studies including: name of first author, publication year, country of origin, ethnicity, and genotype numbers of cases and controls. Two reviewers independently performed the extraction of data and assessed the study quality based on the NOS [27]. All disagreements were discussed and resolved with consensus.

Statistical analysis

All statistical analyses were performed using the Stata 11.0 software (StataCorp, College Station, TX, USA). ORs and 95%CIs were used to assess the strength of associations between TNFAIP3 gene rs10499194, rs13207033 polymorphisms and RA risk. Stratification analysis was carried out by ethnicity. P < 0.05 was considered statistically significant. When a Q test indicated P < 0.1 or I2 > 50% indicated heterogeneity across studies, a random-effect model was used. Otherwise, the fixed-effects model was applied [28]. Pooled ORs were calculated for allele model, dominant model, recessive model, homozygous model, and heterozygous model. We performed sensitivity analyses by omitting each study in turn to determine the effect on the test of heterogeneity and evaluated the stability of the overall results. We assessed the departure from the HWE in the controls using Pearson’s χ2 test. Potential publication bias was assessed by Begger’s and Egger’s linear regression test [29]; P < 0.05 was considered to indicate statistically significant. The power of this meta-analysis was calculated with a significant value of 0.05 [30].

Abbreviations

RA, rheumatoid arthritis; TNFAIP3, tumor necrosis factor alpha inducible protein 3; HLA, Human leukocyte antigen; CI, confidence interval; OR, odds ratio; NOS, Newcastle-Ottawa Scale; HWE, Hardy–Weinberg equilibrium; SNP, single nucleotide polymorphism

ACKNOWLEDGMENTS

This study was supported by National Natural Science Foundation of China, No. 81371927.

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

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