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ORIGINAL ARTICLE
Associations Between PADI4 Gene Polymorphisms and Rheumatoid Arthritis: An Updated Meta-analysis Xiao-ke Yang,* Juan Liu,* Jie Liu, Yan Liang, Wang-dong Xu, Rui-xue Leng, Hai-feng Pan, and Dong-qing Ye
Q2
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China Received for publication December 10, 2014; accepted May 26, 2015 (ARCMED-D-14-00722).
Background and Aims. Studies investigating the association between the peptidylarginine deiminase 4 (PADI4) gene polymorphisms and rheumatoid arthritis (RA) reported conflicting results. The aim of this meta-analysis was to assess the association between PADI4 gene polymorphisms and RA. Methods. A systematic literature search was conducted to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. Results. A total of 34 studies from 28 articles involving 19859 patients with RA and 25771 healthy controls were included. Significant association of PADI4e94G/A polymorphism and RA was observed (OR 5 0.891, 95% CI 5 0.833e0.954, p 5 0.001) in the overall study population and in the Asian populations (OR 5 0.824, 95% CI 5 0.759e0.894, p 5 0.000) respectively. For the e92C/G polymorphism, a significant association was observed (OR 5 1.481, 95% CI 5 1.166e1.882, p 5 0.001) in Africans. For the e90C/T polymorphism, a significant association was observed (OR 5 0.576, 95% CI 5 0.381e0.872, p 5 0.009) in the Latin American population. The pooled estimates for the other polymorphisms were not statistically significantly associated with RA (PADI4e104C/T, e89A/G, e96T/C). Conclusions. This meta-analysis demonstrates that PADI4e94G/A polymorphism is associated with susceptibility to RA in the overall population and in the Asian population. The PADI4 e92C/G polymorphism confers susceptibility to RA in Africans and the PADI4e90C/T polymorphism was associated with RA in the Latin American population. Ó 2015 IMSS. Published by Elsevier Inc. Key Words: PADI4, Rheumatoid arthritis, Polymorphism, Meta-analysis.
Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease of predominantly synovial joints and affects up to 1% of the global population (1). Although the etiology of RA remains unknown, it has been established that susceptibility to RA has a genetic component (2,3). According to the most recent research, human leukocyte antigen (HLA) class II molecules
*
These authors contributed equally to this work. Address reprint requests to: Dong-qing Ye, MD, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China; Phone: þ86 551 65167726; FAX: þ86 551 65161171; E-mail: [email protected]
are considered to be the most powerful genetic factors of RA. However, types of non-HLA gene factors including CTLA4, PTN22, STAT4 and peptidyl arginine deiminase type IV (PADI4), which are also implicated in the predisposition to RA, should never be ignored (4). PADI4 is a member of the PADI gene family, which encodes enzymes that are responsible for the posttranslational conversion of arginine within peptides to citrulline (5). Antibodies to cyclic citrullinated peptides (CCP) are highly specific for RA and often predate the development of disease, suggesting a critical role in RA pathogenesis (6,7). PADI4 mRNA is detected in hematological cells and pathological synovial tissues, and high levels of PADI4 protein are expressed in the inflamed synovium of RA patients
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(8,9). PADI4 is responsible for the fibrin citrullination and participates in apoptosis (10). Suzuki et al. (8) indicated that the PADI4 susceptibility haplotype had significantly increased mRNA stability compared with the nonsusceptibility haplotype. This might be due to elevated levels of PADI4 enzyme, with consequent increased protein citrullination, which may reduce immune tolerance, leading to production of anti-CCP and disease. Further analyses revealed a functional haplotype that affects the stability of PADI4 transcription and is also associated with levels of anti-CCP in the serum of patients with RA (8). Thus, this susceptibility gene, which is involved in the citrullination pathway, is thought to play an essential role in the pathogenesis of RA. The PADI4 gene was located on human chromosome 1p36 (8). Over the last decade, a number of studies have investigated the association between PADI4 gene polymorphisms and RA risk (8,9,11e36). However, the available results remain inconsistent and this discrepancy might be due to studies with small sample size, various racial and ethnic backgrounds, uncorrected multiple hypothesis testing, and publication bias. Meta-analysis could enhance the statistical power and draw a more reliable conclusion in comparison to a single study (37). Iwamoto et al. (38) and Hou et al. (39) both performed meta-analyses to assess the association between PADI4 gene polymorphisms and RA risk. Additional studies concerning the association between SNPs and RA risk have been reported in recent years (29e36). Thus, it seems necessary to perform a meta-analysis that includes the most updated data to investigate the relationships between PADI4 gene polymorphisms and RA. Methods Literature Search A systematic literature search in PubMed, Embase, the China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), and Wanfang (Chinese) was performed to identify articles. The text words are as follows: ‘‘peptidylarginine deiminase 4’’ ‘‘PADI4’’ ‘‘RA’’ and ‘‘rheumatoid arthritis’’. Studies published in English and Chinese were all considered in this meta-analysis. References in these studies were also reviewed to identify additional studies. The last search was updated on July 20, 2014. A total of 117 relevant studies were identified.
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in HardyeWeinberg equilibrium (HWE); e) genotyping methods included TaqMan, PCR, PCR-RFLP and PCR-SSP; f) manuscript publication in a peer-reviewed journal as a full paper. Reviews or abstracts were not accepted. The following exclusion criteria were used: a) studies containing overlapping data; b) studies in which family members had been studied, as their linkage considerations. Data Extraction Two investigators (Xiao-ke Yang and Juan Liu) independently assessed all potentially relevant studies according to the inclusion and exclusion criteria. The following characteristics were extracted from each study: first author, year of publication, country of origin, ethnicity, genotyping methods, number of cases and healthy controls and polymorphisms analyzed in this article. Evaluation of Publication Bias The funnel plot was used to assess potential publication bias and the Egger’s test was applied to evaluate the funnel plot asymmetry, which is an approach to measure funnel plot asymmetry using a natural logarithm scale of the OR (40); p value !0.05 considered significant publication bias. Statistical Analysis Allele frequencies at the PADI4 gene polymorphisms from the individual study were determined by the counting method. HWE was tested using the c2 test (significant at the 0.05 level). The strength of association between the gene polymorphisms and RA susceptibility was assessed with ORs and 95% confidence intervals (CIs). Cochran (Q) and Higgins (I2) tests were generally used to assess the within and between-study variation or heterogeneity (I2 5 100% (Q-df)/Q). A significant Q-statistic ( p !0.10) indicated heterogeneity across studies. I2 values of 25, 50, and 75% were nominally defined as low, moderate, and high estimates. I2 represents the proportion of between-study variability attributable to heterogeneity rather than chance (41,42). If there was no obvious heterogeneity, the fixed-effects model (Mantel-Haenszel method) was used to estimate the summary OR. Otherwise, the random-effects model (DerSimonian and Laird method) was used. All statistical analyses for the meta-analysis were performed with STATA 12.0 software (Stata Corporation, College Station, TX).
Inclusion and Exclusion Criteria Inclusion criteria were defined as follows: a) design was a case-control or cohort study; b) studies evaluated the association between PADI4 gene polymorphisms (PADI4e94G/A, e104C/T, e92C/G, e89A/G, e90C/T, e96T/C) and RA risk; c) sufficient published data to calculate to calculate the odds ratio (OR); d) genotype distribution of the control group is
Results Literature Search and Study Characteristics One hundred seventeen relevant articles were identified, and 35 were selected for full-text review based on their titles and abstracts. Seven articles were excluded: one
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Table 1. Characteristics of the included studies in the present meta-analysis Association First author (reference)
Year
Suzuki (8)
2003
Japan
Asian
823
655
PCR
Harney (9)
2005
UK
European
111
111
PCR
Hoppe (11)
2005
Germany
European
102
102
PCR
Plenge (12) Plenge (12) Martinez (13)
2005 2005 2005
North America Sweden Spain
European European European
1530 840 354
881 876 498
PCR PCR TaqMan
Ikari (14)
2005
Japan
Asian
1230
948
PCR
Chen (15)
2010
China
Asian
378
204
PCR
Takata (16) Burr (17) Burr (17) Abd-Allah (18)
2008 2010 2010 2011
Japan UK UK Egypt
Asian European European African
950 3732 1859 275
507 3039 10599 275
Barton (19)
2004
UK
European
839
481
PCR
Kang (20)
2006
Korea
Asian
545
392
PCR
Costenbader (21) Costenbader (21) Costenbader (21) Po or (22)
2008 2008 2008 2007
USA USA USA Hungary
European European European European
219 169 49 261
219 169 49 120
Kochi (23)
2011
Japan
Asian
1019
907
PCR PCR PCR TaqMan TaqMan PCR
Kochi (23)
2011
Japan
Asian
999
1128
PCR
Kochi (23)
2011
Dutch
European
635
391
PCR
Feng (24) Cui (25)
2010 2007
China China
Asian Asian
115 92
106 116
PCR PCR
Zhong (26) Shi (27)
2010 2010
China China
Asian Asian
302 116
322 100
PCR-RFLP PCR
Cui (28) Li (29)
2011 2012
China China
Asian Asian
134 53
140 42
PCR PCR-SSP
Li (30)
2013
China
Asian
192
288
PCR-RFLP
Country
Ethnicity
Case
Control
Genotyping methods
TaqMan PCR PCR PCR-RFLP
p (allelic contrast) PADI4_92 PADI4_94 PADI4_104 PADI4_92 PADI4_94 PADI4_104 PADI4_89 PADI4_90 PADI4_92 PADI4_94 PADI4_96 PADI4_104 PADI4_94 PADI4_94 PADI4_94 PADI4_104 PADI4_94 PADI4_104 PADI4_89 PADI4_90 PADI4_94 PADI4_104 PADI4_94 PADI4_94 PADI4_94 PADI4_92 PADI4_96 PADI4_89 PADI4_90 PADI4_92 PADI4_104 PADI4_89 PADI4_90 PADI4_92 PADI4_104 PADI4_94 PADI4_94 PADI4_94 PADI4_92 PADI4_104 PADI4_90 PADI4_104 PADI4_90 PADI4_104 PADI4_90 PADI4_104 PADI4_104 PADI4_94 PADI4_104 PADI4_92 PADI4_94 PADI4_104 PADI4_94 PADI4_90 PADI4_92 PADI4_104 PADI4_89 PADI4_92 PADI4_94
0.000 0.000 0.001 0.138 0.390 0.548 0.030 0.030 0.621 0.030 0.755 0.400 0.003 0.918 0.965 0.761 0.001 0.761 0.472 0.549 0.640 0.959 0.025 0.580 0.573 0.001 0.457 0.086 0.122 0.313 0.118 0.000 0.000 0.000 0.002 0.866 0.159 0.934 0.477 0.240 0.062 0.203 0.180 0.174 0.369 0.059 0.252 0.045 0.000 0.113 0.134 0.583 0.038 0.116 0.227 0.003 0.750 NA 0.248
HWE ( p) 0.701 0.829 0.006 0.678 0.989 0.823 NA NA NA NA NA NA 0.058 0.133 0.669 0.881 0.916 0.879 0.235 0.249 0.334 0.407 0.466 0.188 0.929 0.393 0.111 0.658 0.833 0.721 0.786 0.770 0.770 0.938 0.023 0.729 0.362 0.661 0.661 0.342 NA NA NA NA NA NA 0.595 0.250 0.852 0.975 0.185 0.185 0.179 0.014 0.666 0.595 0.019 NA 0.231
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Table 1 (continued ) Association First author (reference)
Year
Panati (31)
2012
India
Asian
Ben (32)
2012
Tunisian
African
Zavala (33)
2013
Mexico
Latin American
Cheng (34)
2012
China
Liu (35)
2012
Du (36)
2014
Country
Ethnicity
Case
Genotyping methods
Control
95
56
PCR
120
125
PCR-RFLP
86
98
PCR-RFLP
Asian
329
697
PCR
China
Asian
90
90
PCR
China
Asian
1216
1040
deviated from HWE (43) and six did not provide sufficient or available data for our analysis (44e49). Thus, 28 articles met our inclusion criteria (8,9,11e36). Among the eligible articles, four articles (12,17,21,23) contained data on two or more different groups, and these groups were analyzed independently. Finally, a total of 34 studies in 28 articles including 19859 cases and 25771 controls
TaqMan
p (allelic contrast) PADI4_89 PADI4_90 PADI4_92 PADI4_104 PADI4_94 PADI4_96 PADI4_89 PADI4_90 PADI4_92 PADI4_92 PADI4_94 PADI4_92 PADI4_94 PADI4_104 PADI4_94 PADI4_104
HWE ( p)
0.605 0.605 0.084 0.000 0.236 0.759 0.077 0.010 0.729 0.028 0.009 0.887 0.473 0.775 0.001 0.001
NA NA NA NA 0.424 0.742 0.191 0.113 0.086 0.803 0.751 0.071 0.533 0.601 0.033 0.036
were considered in our meta-analysis (8,9,11e36). There were 22 studies on e94G/A, 19 studies on e104C/T, 14 studies on. e92C/G, seven studies on e89A/G, ten studies on e90C/T, and three studies on e96T/C. The main characteristics of each study included in this meta-analysis are listed in Table 1.
Table 2. Meta-analysis of PADI4 polymorphisms and RA susceptibility Sample size Polymorphisms PADI4_94G/A G vs. A allele
PADI4_92C/G C vs. G allele
PADI4_104C/T C vs. T allele PADI4_89A/G A vs. G allele
PADI4_90C/T C vs. T allele
PADI4_96T/C T vs. C allele
Test of association
Test of heterogeneity
Population
Number of studies
Case
Control
OR
95%CI
p
Model
Q
p
I2 (%)
Egger’s test ( p)
Overall Asian European African Overall Asian European Latin American African Overall Asian European Overall Asian European Latin American Overall Asian European Latin American Overall African European
22 11 10 1 14 8 4 1 1 19 13 6 7 4 2 1 10 6 3 1 3 2 1
14635 5550 8965 120 4103 2429 1313 86 275 9072 6770 2302 2237 1210 941 86 4762 3089 1587 86 497 395 102
21453 4785 16543 125 3729 2542 814 98 275 7484 5781 1703 1621 940 583 98 3795 2729 968 98 502 400 102
0.891 0.824 0.969 0.806 1.069 0.989 1.121 0.93 1.481 0.927 0.930 0.909 1 0.94 1.269 0.687 0.958 0.922 1.121 0.576 0.949 0.922 1.067
0.833e0.954 0.759e0.894 0.903e1.041 0.566e1.150 0.913e1.252 0.765e1.279 0.986e1.274 0.616e1.404 1.166e1.882 0.839e1.024 0.813e1.064 0.826e1.001 0.796e1.255 0.702e1.260 0.977e1.647 0.455e1.037 0.833e1.103 0.785e1.084 0.885e1.419 0.381e0.872 0.792e1.137 0.754e1.128 0.710e1.605
0.001 0.000 0.390 0.235 0.406 0.932 0.082 0.728 0.001 0.136 0.293 0.052 0.998 0.681 0.074 0.074 0.553 0.328 0.346 0.009 0.569 0.431 0.755
R R R NA R R R NA NA R R R R R F NA R R R NA F F NA
60.89 17.41 16.33 0.00 54.59 42.83 0.98 0.00 0.00 68.35 63.20 4.56 29.89 14.49 1.75 0.00 35.97 17.02 6.67 0.00 0.42 0.03 0.00
0.000 0.066 0.060 NA 0.000 0.000 0.806 NA NA 0.000 0.000 0.472 0.000 0.002 0.186 NA 0.000 0.004 0.036 NA 0.810 0.868 NA
65.50 42.60 44.90 NA 78.00 86.00 0.00 NA NA 73.70 81.00 0.00 79.90 79.30 42.90 NA 75.00 70.60 70.00 NA 0.00 0.00 NA
0.289 0.549 0.844 NA 0.901 0.917 0.338 NA NA 0.109 0.249 0.193 0.710 0.328 NA NA 0.446 0.374 0.527 NA 0.313 NA NA
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Meta-analysis of PADI4 Gene Polymorphisms and RA
Meta-analysis of PADI 4 Gene Polymorphisms in Rheumatoid Arthritis The summary of the meta-analysis of the relationship between PADI4 gene polymorphisms and RA is shown in Table 2.
Figure 1). Stratification by ethnicity indicated that the e94G allele was significantly associated with RA risk in the Asian population (OR 5 0.824, 95% CI 5 0.759e0.894, p !0.001, Figure 1). PADI4e92C/G Polymorphism and Rheumatoid Arthritis
PADI4e94G/A Polymorphism and Rheumatoid Arthritis Twenty two studies determined the relationship between the PADI4e94G/A polymorphism and RA risk (8,9, 11e17,21,25,27,28,30,32,34e36). The total sample size for patients with RA and healthy controls was 14635 and 21453, respectively. Meta-analysis revealed an association between PADI4e94G and RA risk in the overall population (OR 5 0.891, 95% CI 5 0.833e0.954, p 5 0.001,
Fourteen studies including 4103 cases and 3729 controls identified an association between the PADI4e92C/G polymorphism and RA risk (8,9,11,18e20,22,26,29e31,33 e35). No significant association of PADI4e92C allele with genetic susceptibility to RA was detected in the overall population. When stratified by ethnicity, a significant association was observed in the African population (OR 5 1.481, 95% CI 5 1.166e1.882, p 5 0.001, Figure 2).
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Figure 1. Odds ratios and 95% confidence intervals for individual studies and pooled data for the association between the G vs. A allele of the PADI4e94G/A polymorphism and rheumatoid arthritis.
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Figure 2. Odds ratios and 95% confidence intervals for individual studies and pooled data for the association between the C vs. G allele of the PADI4e92C/G polymorphism and rheumatoid arthritis.
PADI4e90C/T Polymorphism and Rheumatoid Arthritis Ten studies containing 4762 cases and 3795 controls examined the association of PADI4e90C/T and RA (11, 15,19,20,23,29,31,33). Results indicated a significant association between the PADI4e90C/T polymorphism and RA. In the subgroup analysis by ethnicity, we found a significant association in the Latin American population (OR 5 0.576, 95% CI 5 0.381e0.872, p 5 0.009, Figure 3). PADI4e104C/T, e89A/G, e96T/C Polymorphism and Rheumatoid Arthritis No association was detected between PADI4e104C/T (19 studies, 9072 cases and 7487 controls), e89A/G (7 studies, 2237 cases and 1621 controls), 96T/C (three studies, 497
cases and 502 controls) polymorphism and RA risk in the overall population. After stratifying by ethnicity, the results also showed that these polymorphisms were not associated with RA risk in any of the subgroups. Heterogeneity and Publication Bias Heterogeneity of the included studies regarding each polymorphism is presented in Table 2. Heterogeneity was found among the PADI4e94G/A. e92C/G, e104C/T, e89A/G and e90C/T polymorphisms in the overall group and some subgroup study subjects. Thus, these meta-analyses were performed using the random-effects model, another meta-analysis was performed using the fixed-effects model.
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Meta-analysis of PADI4 Gene Polymorphisms and RA
Figure 3. Odds ratios and 95% confidence intervals for individual studies and pooled data for the association between the C vs. T allele of the PADI4e90C/T polymorphism and rheumatoid arthritis.
To explore potential sources of heterogeneity in this meta-analysis, meta-regression analysis was performed. Confounding factors included sample size, ethnicity, publication year, and genotyping method. The results showed that these potential factors were all probably not the major sources of heterogeneity (all p value for regression O0.05). The funnel plot and Egger’s test were performed to access publication bias. In the present study, no publication bias was found (Table 2). Discussion Although the multifactorial nature of RA is well known, genetic factors are considered to be strong determinants of these diseases, thus encouraging researchers to search for the responsible genes. PADI4 has been implicated in the pathogenesis, activity and severity of RA (45,48). Recently, investigations on the relationship between PADI4 gene polymorphisms and RA have been extensively performed in different populations. However, results of individual studies were inconclusive. Takata et al. (16)
observed that PADI4e94 was modestly associated with RA. Cheng et al. (34) also suggested that the functional single-nucleotide polymorphism (SNP) PADI4e94G/A variant allele is associated with RA development. In contrast, Chen et al. (15) discovered no significant difference in the allele frequency of PADI4e94G/A between patients with RA and controls in Chinese. To comprehensively analyze these associations between PADI4 gene polymorphisms and RA susceptibility, a meta-analysis was performed. Compared with the previous meta-analysis (38,39), the current study involved more research (28 articles, 34 studies). This is the first meta-analysis to investigate the association between the PADI4_96T/C polymorphism and RA susceptibility. This is also the first meta-analysis to include an African population and three PADI4 gene loci (PADI4_94, PADI4_92, PADI4_96), Latin American population and three PADI4 gene loci (PADI4_92, PADI4_89, PADI4_90). In addition, we excluded studies in which HWE was absent in the controls. As several studies have reported significant associations between genetic polymorphisms and diseases
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when the genotype distribution of the control population deviated from HWE, deviation from HWE in the control population might imply potential selection biases of controls or genotype errors. Therefore, our meta-analysis might draw a more reliable conclusion. The overall results demonstrated that PADI4e94G/A polymorphism was significantly associated with RA susceptibility. However, we failed to detect an association between PADI4e92C/G, PADI4e104C/T, PADI4e89A/G, PADI4e90C/T and PADI4e96T/C polymorphisms and RA risk. In the present study, we also performed subgroup analyses by ethnicity for these polymorphisms. Our results revealed that the PADI4e94G/A polymorphism was associated with RA in Asians, but not in Europeans. These results were very different from those observed by Iwamoto et al. (38) and Hou et al. (39) in the previous meta-analysis. Furthermore, in this meta-analysis we found the PADI4e92C/G polymorphism was associated with RA in Africans, whereas the PADI4e90C/T polymorphism was associated with RA in Latin Americans. However, this might not be reliable because only one published article in each of the two groups was included in the present study. Therefore, additional large sample size case-control studies should be performed in these two groups. Some potential limitations of this meta-analysis should be acknowledged. First, this study could not analyze the potential gene-environment interactions and gene susceptibility haplotypes due to limited data, such as data on environmental risk factors and genotypes. Second, our literature search was dependent on English and Chinese; therefore, language bias might be considered. Third, although we used random-effect models to pool ORs if significant heterogeneities between studies were observed in comparisons, heterogeneities and confounding factors still exist and may distort the meta-analysis. Fourth, different genotyping methods and disease status might affect the interpretation of the data of included studies. Finally, meta-analysis remains a retrospective research subject to the methodological deficiencies of the included studies. In conclusion, this updated meta-analysis demonstrates that PADI4e94G might be risk alleles for RA susceptibility, especially in Asians. It has also been detected that PADI4e92C/G polymorphism confers susceptibility to RA in Africans and the PADI4e90C/T polymorphism was associated with RA in Latin Americans. However, large-scale studies including more ethnic groups with careful matching between cases and controls should be considered to further explore the relationship between polymorphisms in the PADI4 genes and the pathogenesis of RA. Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (81271759).
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References 1. Lee YH, Bae SC, Choi SJ, et al. Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis. Mol Biol Rep 2012;39:10627e10635. 2. Song GG, Bae SC, Lee YH. Associations between functional TNFR2 196 M/R polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Rheumatol Int 2014;34:1529e1537. 3. Mohan VK, Ganesan N, Gopalakrishnan R. Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis. J Genet 2014;93:597e605. 4. Kurko J, Besenyei T, Laki J, et al. Genetics of rheumatoid arthritis—a comprehensive review. Clin Rev Allergy Immunol 2013;45:170e179. 5. Zhou Z, Menard HA. Autoantigenic posttranslational modifications of proteins: does it apply to rheumatoid arthritis? Curr Opin Rheumatol 2002;14:250e253. 6. Kinloch A, Lundberg K, Wait R, et al. Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. Arthritis Rheum 2008;58:2287e2295. 7. Chang X, Zhao Y, Sun S, et al. The expression of PADI4 in synovium of rheumatoid arthritis. Rheumatol Int 2009;29:1411e1416. 8. Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34:395e402. 9. Harney SM, Meisel C, Sims AM, et al. Genetic and genomic studies of PADI4 in rheumatoid arthritis. Rheumatology (Oxford) 2005;44: 869e872. 10. Chang X, Yamada R, Suzuki A, et al. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology 2005;44:40e50. 11. Hoppe B, Haupl T, Gruber R, et al. Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a caseecontrol study. Arthritis Res Ther 2006;8:R34. 12. Plenge RM, Padyukov L, Remmers EF, et al. Replication of putative candidate-gene associations with rheumatoid arthritis in O4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 2005;77: 1044e1060. 13. Martinez A, Valdivia A, Pascual-Salcedo D, et al. PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford) 2005;44:1263e1266. 14. Ikari K, Kuwahara M, Nakamura T, et al. Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum 2005;52: 3054e3057. 15. Chen R, Wei Y, Cai Q, et al. The PADI4 gene does not contribute to genetic susceptibility to rheumatoid arthritis in Chinese Han population. Rheumatol Int 2011;31:1631e1634. 16. Takata Y, Inoue H, Sato A, et al. Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with rheumatoid arthritis: results of an independent Japanese population and evidence from meta-analysis of East Asian studies. J Hum Genet 2008;53:163e173. 17. Burr ML, Naseem H, Hinks A, et al. PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population. Ann Rheum Dis 2010;69:666e670. 18. Abd-Allah SH, el-Shal AS, Shalaby SM, et al. PADI4 polymorphisms and related haplotype in rheumatoid arthritis patients. Joint Bone Spine 2012;79:124e128. 19. Barton A, Bowes J, Eyre S, et al. A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 2004;50:1117e1121. 20. Kang CP, Lee HS, Ju H, et al. A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum 2006;54:90e96.
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21. Costenbader KH, Chang SC, De Vivo I, et al. Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of geneeenvironment interactions with heavy cigarette smoking. Arthritis Res Ther 2008;10:R52. 22. Po or G, Nagy ZB, Schmidt Z, et al. Genetic background of anticyclic citrullinated peptide autoantibody production in Hungarian patients with rheumatoid arthritis. Ann N Y Acad Sci 2007;1110:23e32. 23. Kochi Y, Thabet MM, Suzuki A, et al. PADI4 polymorphism predisposes male smokers to rheumatoid arthritis. Ann Rheum Dis 2011; 70:512e515. 24. Feng ZJ, Niu HZ, Liang Y, et al. Association between rheumatoid arthritis and single nucleotide polymorphisms of padi4e104 in Han population in Hebei province. J Mol Diagn Ther 2010;2:244e247. (in Chinese). 25. Cui LF, Yang WH, Song HC, et al. Association of polymorphism of peptidylarginine deiminase 4 gene and rheumatoid arthritis in Han population. Chin J Allergy Clin Immunol 2007;1:158e162. (in Chinese). 26. Zhong B, Fang YF, Li H, et al. Correlation of peptidylarginine deiminase 4 gene polymorphism and rheumatoid arthritis. J Third Militar Med Univ 2010;32:1155e1157. (in Chinese). 27. Shi HX, Qian L, Li XP, et al. Association of polymorphism of peptidylarginine deaminase-4 gene and rheumatoid arthritis. Chin J Rheumatol 2010;14:336e339. (in Chinese). 28. Cui LF, Yuan W, Yang WH, et al. Association of polymorphism of peptidylarginine deiminase 4 (PADI4) gene with rheumatoid arthritis and anti-cyclic citrullinated peptide antibody. Chin J Basic Med Tradit Chin Med 2011;17:630e632. (in Chinese). 29. Li HB, Tie N, Jia YF, et al. Association between the synovial expression of cyclic citrallinated petide and susceptibility variants of HLA-DRB1 shared epitope alleles and PADI 4 gene single nucleotide polymorphism in patients with rheumatoid arthritis. Natl Med J China 2012;92:1607e1611. (in Chinese). 30. Li Q, Lin KQ, Li Q, et al. Association of polymorphism of PTPN22 and PADI4 genes with rheumatoid arthritis in Yunnan. Chin J Med Genet 2013;30:111e115. (in Chinese). 31. Panati K, Pal S, Rao KV, et al. Association of single nucleotide polymorphisms (SNPs) of PADI4 gene with rheumatoid arthritis (RA) in Indian population. Genes Genet Syst 2012;87:191e196. 32. Ben Hassine H, Zemni R, Bouagina E, et al. Lack of association between PADI4 polymorphisms and rheumatoid arthritis in the Tunisian population. Joint Bone Spine 2012;79:329e330. 33. Zavala-Cerna MG, Gonzalez-Montoya NG, Nava A, et al. PADI4 haplotypes in association with RA Mexican patients, a new prospect for antigen modulation. Clin Dev Immunol 2013;2013:383681. 34. Cheng J, Zhang H, Zhuang C, et al. Peptidylarginine deiminase type 4 and methyl-CpG binding domain 4 polymorphisms in Chinese patients with rheumatoid arthritis. J Rheumatol 2012;39:1159e1165.
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35. Liu Y, Yang FM, Zhang PL, et al. Correlation between PADI4 gene polymorphisms and rheumatoid arthritis in Han, Hui and Tibetan people of plateau area. Chin J Gerontol 2012;32:3881e3883. (in Chinese). 36. Du Y, Liu X, Guo JP, et al. Association between PADI4 gene polymorphisms and anti-cyclic citrullinated peptide antibody positive rheumatoid arthritis in a large Chinese Han cohort. Clin Exp Rheumatol 2014; 32:377e382. 37. Xu WD, Peng H, Zhou M, et al. Association of RANTES and MBL gene polymorphisms with systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 2013;40:941e948. 38. Iwamoto T, Ikari K, Nakamura T, et al. Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford) 2006;45:804e807. 39. Hou S, Gao GP, Zhang XJ, et al. PADI4 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Mod Rheumatol 2013;23:50e60. 40. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629e634. 41. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539e1558. 42. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557e560. 43. Fan LY, Wang WJ, Wang Q, et al. A functional haplotype and expression of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Chinese. Tissue Antigens 2008;72:469e473. 44. Chang X, Xia Y, Pan J, et al. PADI2 is significantly associated with rheumatoid arthritis. PLoS One 2013;8:e81259. 45. Suzuki T, Ikari K, Yano K, et al. PADI4 and HLA-DRB1 Are genetic risks for radiographic progression in RA patients, independent of ACPA status: Results from the IORRA Cohort Study. PLoS One 2013;8: e61045. 46. Meziani R, Yamada R, Takahashi M, et al. A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations. Mod Rheumatol 2012;22:52e58. 47. Prasad P, Kumar A, Gupta R, et al. Caucasian and Asian specific rheumatoid arthritis risk loci reveal limited replication and apparent allelic heterogeneity in North Indians. PLoS One 2012;7:e31584. 48. Ceccarelli F, D’Alfonso S, Perricone C, et al. The role of eight polymorphisms in three candidate genes in determining the susceptibility, phenotype, and response to anti-TNF therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol 2012;30:939e942. 49. Liu Y, Yang FM, Li R, et al. Anti-cyclic citrullinated peptide antibody and serum peptidylarginine deiminase polymorphism in rheumatoid arthritis patients in Qinghai Hui population. Chin Gen Practice 2012;15:3734e3736. (in Chinese).
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ORIGINAL ARTICLE
Associations Between PADI4 Gene Polymorphisms and Rheumatoid Arthritis: An Updated Meta-analysis Xiao-ke Yang,* Juan Liu,* Jie Liu, Yan Liang, Wang-dong Xu, Rui-xue Leng, Hai-feng Pan, and Dong-qing Ye
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Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China Received for publication December 10, 2014; accepted May 26, 2015 (ARCMED-D-14-00722).
Background and Aims. Studies investigating the association between the peptidylarginine deiminase 4 (PADI4) gene polymorphisms and rheumatoid arthritis (RA) reported conflicting results. The aim of this meta-analysis was to assess the association between PADI4 gene polymorphisms and RA. Methods. A systematic literature search was conducted to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. Results. A total of 34 studies from 28 articles involving 19859 patients with RA and 25771 healthy controls were included. Significant association of PADI4e94G/A polymorphism and RA was observed (OR 5 0.891, 95% CI 5 0.833e0.954, p 5 0.001) in the overall study population and in the Asian populations (OR 5 0.824, 95% CI 5 0.759e0.894, p 5 0.000) respectively. For the e92C/G polymorphism, a significant association was observed (OR 5 1.481, 95% CI 5 1.166e1.882, p 5 0.001) in Africans. For the e90C/T polymorphism, a significant association was observed (OR 5 0.576, 95% CI 5 0.381e0.872, p 5 0.009) in the Latin American population. The pooled estimates for the other polymorphisms were not statistically significantly associated with RA (PADI4e104C/T, e89A/G, e96T/C). Conclusions. This meta-analysis demonstrates that PADI4e94G/A polymorphism is associated with susceptibility to RA in the overall population and in the Asian population. The PADI4 e92C/G polymorphism confers susceptibility to RA in Africans and the PADI4e90C/T polymorphism was associated with RA in the Latin American population. Ó 2015 IMSS. Published by Elsevier Inc. Key Words: PADI4, Rheumatoid arthritis, Polymorphism, Meta-analysis.
Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease of predominantly synovial joints and affects up to 1% of the global population (1). Although the etiology of RA remains unknown, it has been established that susceptibility to RA has a genetic component (2,3). According to the most recent research, human leukocyte antigen (HLA) class II molecules
*
These authors contributed equally to this work. Address reprint requests to: Dong-qing Ye, MD, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China; Phone: þ86 551 65167726; FAX: þ86 551 65161171; E-mail: [email protected]
are considered to be the most powerful genetic factors of RA. However, types of non-HLA gene factors including CTLA4, PTN22, STAT4 and peptidyl arginine deiminase type IV (PADI4), which are also implicated in the predisposition to RA, should never be ignored (4). PADI4 is a member of the PADI gene family, which encodes enzymes that are responsible for the posttranslational conversion of arginine within peptides to citrulline (5). Antibodies to cyclic citrullinated peptides (CCP) are highly specific for RA and often predate the development of disease, suggesting a critical role in RA pathogenesis (6,7). PADI4 mRNA is detected in hematological cells and pathological synovial tissues, and high levels of PADI4 protein are expressed in the inflamed synovium of RA patients
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(8,9). PADI4 is responsible for the fibrin citrullination and participates in apoptosis (10). Suzuki et al. (8) indicated that the PADI4 susceptibility haplotype had significantly increased mRNA stability compared with the nonsusceptibility haplotype. This might be due to elevated levels of PADI4 enzyme, with consequent increased protein citrullination, which may reduce immune tolerance, leading to production of anti-CCP and disease. Further analyses revealed a functional haplotype that affects the stability of PADI4 transcription and is also associated with levels of anti-CCP in the serum of patients with RA (8). Thus, this susceptibility gene, which is involved in the citrullination pathway, is thought to play an essential role in the pathogenesis of RA. The PADI4 gene was located on human chromosome 1p36 (8). Over the last decade, a number of studies have investigated the association between PADI4 gene polymorphisms and RA risk (8,9,11e36). However, the available results remain inconsistent and this discrepancy might be due to studies with small sample size, various racial and ethnic backgrounds, uncorrected multiple hypothesis testing, and publication bias. Meta-analysis could enhance the statistical power and draw a more reliable conclusion in comparison to a single study (37). Iwamoto et al. (38) and Hou et al. (39) both performed meta-analyses to assess the association between PADI4 gene polymorphisms and RA risk. Additional studies concerning the association between SNPs and RA risk have been reported in recent years (29e36). Thus, it seems necessary to perform a meta-analysis that includes the most updated data to investigate the relationships between PADI4 gene polymorphisms and RA. Methods Literature Search A systematic literature search in PubMed, Embase, the China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), and Wanfang (Chinese) was performed to identify articles. The text words are as follows: ‘‘peptidylarginine deiminase 4’’ ‘‘PADI4’’ ‘‘RA’’ and ‘‘rheumatoid arthritis’’. Studies published in English and Chinese were all considered in this meta-analysis. References in these studies were also reviewed to identify additional studies. The last search was updated on July 20, 2014. A total of 117 relevant studies were identified.
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in HardyeWeinberg equilibrium (HWE); e) genotyping methods included TaqMan, PCR, PCR-RFLP and PCR-SSP; f) manuscript publication in a peer-reviewed journal as a full paper. Reviews or abstracts were not accepted. The following exclusion criteria were used: a) studies containing overlapping data; b) studies in which family members had been studied, as their linkage considerations. Data Extraction Two investigators (Xiao-ke Yang and Juan Liu) independently assessed all potentially relevant studies according to the inclusion and exclusion criteria. The following characteristics were extracted from each study: first author, year of publication, country of origin, ethnicity, genotyping methods, number of cases and healthy controls and polymorphisms analyzed in this article. Evaluation of Publication Bias The funnel plot was used to assess potential publication bias and the Egger’s test was applied to evaluate the funnel plot asymmetry, which is an approach to measure funnel plot asymmetry using a natural logarithm scale of the OR (40); p value !0.05 considered significant publication bias. Statistical Analysis Allele frequencies at the PADI4 gene polymorphisms from the individual study were determined by the counting method. HWE was tested using the c2 test (significant at the 0.05 level). The strength of association between the gene polymorphisms and RA susceptibility was assessed with ORs and 95% confidence intervals (CIs). Cochran (Q) and Higgins (I2) tests were generally used to assess the within and between-study variation or heterogeneity (I2 5 100% (Q-df)/Q). A significant Q-statistic ( p !0.10) indicated heterogeneity across studies. I2 values of 25, 50, and 75% were nominally defined as low, moderate, and high estimates. I2 represents the proportion of between-study variability attributable to heterogeneity rather than chance (41,42). If there was no obvious heterogeneity, the fixed-effects model (Mantel-Haenszel method) was used to estimate the summary OR. Otherwise, the random-effects model (DerSimonian and Laird method) was used. All statistical analyses for the meta-analysis were performed with STATA 12.0 software (Stata Corporation, College Station, TX).
Inclusion and Exclusion Criteria Inclusion criteria were defined as follows: a) design was a case-control or cohort study; b) studies evaluated the association between PADI4 gene polymorphisms (PADI4e94G/A, e104C/T, e92C/G, e89A/G, e90C/T, e96T/C) and RA risk; c) sufficient published data to calculate to calculate the odds ratio (OR); d) genotype distribution of the control group is
Results Literature Search and Study Characteristics One hundred seventeen relevant articles were identified, and 35 were selected for full-text review based on their titles and abstracts. Seven articles were excluded: one
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Table 1. Characteristics of the included studies in the present meta-analysis Association First author (reference)
Year
Suzuki (8)
2003
Japan
Asian
823
655
PCR
Harney (9)
2005
UK
European
111
111
PCR
Hoppe (11)
2005
Germany
European
102
102
PCR
Plenge (12) Plenge (12) Martinez (13)
2005 2005 2005
North America Sweden Spain
European European European
1530 840 354
881 876 498
PCR PCR TaqMan
Ikari (14)
2005
Japan
Asian
1230
948
PCR
Chen (15)
2010
China
Asian
378
204
PCR
Takata (16) Burr (17) Burr (17) Abd-Allah (18)
2008 2010 2010 2011
Japan UK UK Egypt
Asian European European African
950 3732 1859 275
507 3039 10599 275
Barton (19)
2004
UK
European
839
481
PCR
Kang (20)
2006
Korea
Asian
545
392
PCR
Costenbader (21) Costenbader (21) Costenbader (21) Po or (22)
2008 2008 2008 2007
USA USA USA Hungary
European European European European
219 169 49 261
219 169 49 120
Kochi (23)
2011
Japan
Asian
1019
907
PCR PCR PCR TaqMan TaqMan PCR
Kochi (23)
2011
Japan
Asian
999
1128
PCR
Kochi (23)
2011
Dutch
European
635
391
PCR
Feng (24) Cui (25)
2010 2007
China China
Asian Asian
115 92
106 116
PCR PCR
Zhong (26) Shi (27)
2010 2010
China China
Asian Asian
302 116
322 100
PCR-RFLP PCR
Cui (28) Li (29)
2011 2012
China China
Asian Asian
134 53
140 42
PCR PCR-SSP
Li (30)
2013
China
Asian
192
288
PCR-RFLP
Country
Ethnicity
Case
Control
Genotyping methods
TaqMan PCR PCR PCR-RFLP
p (allelic contrast) PADI4_92 PADI4_94 PADI4_104 PADI4_92 PADI4_94 PADI4_104 PADI4_89 PADI4_90 PADI4_92 PADI4_94 PADI4_96 PADI4_104 PADI4_94 PADI4_94 PADI4_94 PADI4_104 PADI4_94 PADI4_104 PADI4_89 PADI4_90 PADI4_94 PADI4_104 PADI4_94 PADI4_94 PADI4_94 PADI4_92 PADI4_96 PADI4_89 PADI4_90 PADI4_92 PADI4_104 PADI4_89 PADI4_90 PADI4_92 PADI4_104 PADI4_94 PADI4_94 PADI4_94 PADI4_92 PADI4_104 PADI4_90 PADI4_104 PADI4_90 PADI4_104 PADI4_90 PADI4_104 PADI4_104 PADI4_94 PADI4_104 PADI4_92 PADI4_94 PADI4_104 PADI4_94 PADI4_90 PADI4_92 PADI4_104 PADI4_89 PADI4_92 PADI4_94
0.000 0.000 0.001 0.138 0.390 0.548 0.030 0.030 0.621 0.030 0.755 0.400 0.003 0.918 0.965 0.761 0.001 0.761 0.472 0.549 0.640 0.959 0.025 0.580 0.573 0.001 0.457 0.086 0.122 0.313 0.118 0.000 0.000 0.000 0.002 0.866 0.159 0.934 0.477 0.240 0.062 0.203 0.180 0.174 0.369 0.059 0.252 0.045 0.000 0.113 0.134 0.583 0.038 0.116 0.227 0.003 0.750 NA 0.248
HWE ( p) 0.701 0.829 0.006 0.678 0.989 0.823 NA NA NA NA NA NA 0.058 0.133 0.669 0.881 0.916 0.879 0.235 0.249 0.334 0.407 0.466 0.188 0.929 0.393 0.111 0.658 0.833 0.721 0.786 0.770 0.770 0.938 0.023 0.729 0.362 0.661 0.661 0.342 NA NA NA NA NA NA 0.595 0.250 0.852 0.975 0.185 0.185 0.179 0.014 0.666 0.595 0.019 NA 0.231
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Table 1 (continued ) Association First author (reference)
Year
Panati (31)
2012
India
Asian
Ben (32)
2012
Tunisian
African
Zavala (33)
2013
Mexico
Latin American
Cheng (34)
2012
China
Liu (35)
2012
Du (36)
2014
Country
Ethnicity
Case
Genotyping methods
Control
95
56
PCR
120
125
PCR-RFLP
86
98
PCR-RFLP
Asian
329
697
PCR
China
Asian
90
90
PCR
China
Asian
1216
1040
deviated from HWE (43) and six did not provide sufficient or available data for our analysis (44e49). Thus, 28 articles met our inclusion criteria (8,9,11e36). Among the eligible articles, four articles (12,17,21,23) contained data on two or more different groups, and these groups were analyzed independently. Finally, a total of 34 studies in 28 articles including 19859 cases and 25771 controls
TaqMan
p (allelic contrast) PADI4_89 PADI4_90 PADI4_92 PADI4_104 PADI4_94 PADI4_96 PADI4_89 PADI4_90 PADI4_92 PADI4_92 PADI4_94 PADI4_92 PADI4_94 PADI4_104 PADI4_94 PADI4_104
HWE ( p)
0.605 0.605 0.084 0.000 0.236 0.759 0.077 0.010 0.729 0.028 0.009 0.887 0.473 0.775 0.001 0.001
NA NA NA NA 0.424 0.742 0.191 0.113 0.086 0.803 0.751 0.071 0.533 0.601 0.033 0.036
were considered in our meta-analysis (8,9,11e36). There were 22 studies on e94G/A, 19 studies on e104C/T, 14 studies on. e92C/G, seven studies on e89A/G, ten studies on e90C/T, and three studies on e96T/C. The main characteristics of each study included in this meta-analysis are listed in Table 1.
Table 2. Meta-analysis of PADI4 polymorphisms and RA susceptibility Sample size Polymorphisms PADI4_94G/A G vs. A allele
PADI4_92C/G C vs. G allele
PADI4_104C/T C vs. T allele PADI4_89A/G A vs. G allele
PADI4_90C/T C vs. T allele
PADI4_96T/C T vs. C allele
Test of association
Test of heterogeneity
Population
Number of studies
Case
Control
OR
95%CI
p
Model
Q
p
I2 (%)
Egger’s test ( p)
Overall Asian European African Overall Asian European Latin American African Overall Asian European Overall Asian European Latin American Overall Asian European Latin American Overall African European
22 11 10 1 14 8 4 1 1 19 13 6 7 4 2 1 10 6 3 1 3 2 1
14635 5550 8965 120 4103 2429 1313 86 275 9072 6770 2302 2237 1210 941 86 4762 3089 1587 86 497 395 102
21453 4785 16543 125 3729 2542 814 98 275 7484 5781 1703 1621 940 583 98 3795 2729 968 98 502 400 102
0.891 0.824 0.969 0.806 1.069 0.989 1.121 0.93 1.481 0.927 0.930 0.909 1 0.94 1.269 0.687 0.958 0.922 1.121 0.576 0.949 0.922 1.067
0.833e0.954 0.759e0.894 0.903e1.041 0.566e1.150 0.913e1.252 0.765e1.279 0.986e1.274 0.616e1.404 1.166e1.882 0.839e1.024 0.813e1.064 0.826e1.001 0.796e1.255 0.702e1.260 0.977e1.647 0.455e1.037 0.833e1.103 0.785e1.084 0.885e1.419 0.381e0.872 0.792e1.137 0.754e1.128 0.710e1.605
0.001 0.000 0.390 0.235 0.406 0.932 0.082 0.728 0.001 0.136 0.293 0.052 0.998 0.681 0.074 0.074 0.553 0.328 0.346 0.009 0.569 0.431 0.755
R R R NA R R R NA NA R R R R R F NA R R R NA F F NA
60.89 17.41 16.33 0.00 54.59 42.83 0.98 0.00 0.00 68.35 63.20 4.56 29.89 14.49 1.75 0.00 35.97 17.02 6.67 0.00 0.42 0.03 0.00
0.000 0.066 0.060 NA 0.000 0.000 0.806 NA NA 0.000 0.000 0.472 0.000 0.002 0.186 NA 0.000 0.004 0.036 NA 0.810 0.868 NA
65.50 42.60 44.90 NA 78.00 86.00 0.00 NA NA 73.70 81.00 0.00 79.90 79.30 42.90 NA 75.00 70.60 70.00 NA 0.00 0.00 NA
0.289 0.549 0.844 NA 0.901 0.917 0.338 NA NA 0.109 0.249 0.193 0.710 0.328 NA NA 0.446 0.374 0.527 NA 0.313 NA NA
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Meta-analysis of PADI4 Gene Polymorphisms and RA
Meta-analysis of PADI 4 Gene Polymorphisms in Rheumatoid Arthritis The summary of the meta-analysis of the relationship between PADI4 gene polymorphisms and RA is shown in Table 2.
Figure 1). Stratification by ethnicity indicated that the e94G allele was significantly associated with RA risk in the Asian population (OR 5 0.824, 95% CI 5 0.759e0.894, p !0.001, Figure 1). PADI4e92C/G Polymorphism and Rheumatoid Arthritis
PADI4e94G/A Polymorphism and Rheumatoid Arthritis Twenty two studies determined the relationship between the PADI4e94G/A polymorphism and RA risk (8,9, 11e17,21,25,27,28,30,32,34e36). The total sample size for patients with RA and healthy controls was 14635 and 21453, respectively. Meta-analysis revealed an association between PADI4e94G and RA risk in the overall population (OR 5 0.891, 95% CI 5 0.833e0.954, p 5 0.001,
Fourteen studies including 4103 cases and 3729 controls identified an association between the PADI4e92C/G polymorphism and RA risk (8,9,11,18e20,22,26,29e31,33 e35). No significant association of PADI4e92C allele with genetic susceptibility to RA was detected in the overall population. When stratified by ethnicity, a significant association was observed in the African population (OR 5 1.481, 95% CI 5 1.166e1.882, p 5 0.001, Figure 2).
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Figure 1. Odds ratios and 95% confidence intervals for individual studies and pooled data for the association between the G vs. A allele of the PADI4e94G/A polymorphism and rheumatoid arthritis.
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Figure 2. Odds ratios and 95% confidence intervals for individual studies and pooled data for the association between the C vs. G allele of the PADI4e92C/G polymorphism and rheumatoid arthritis.
PADI4e90C/T Polymorphism and Rheumatoid Arthritis Ten studies containing 4762 cases and 3795 controls examined the association of PADI4e90C/T and RA (11, 15,19,20,23,29,31,33). Results indicated a significant association between the PADI4e90C/T polymorphism and RA. In the subgroup analysis by ethnicity, we found a significant association in the Latin American population (OR 5 0.576, 95% CI 5 0.381e0.872, p 5 0.009, Figure 3). PADI4e104C/T, e89A/G, e96T/C Polymorphism and Rheumatoid Arthritis No association was detected between PADI4e104C/T (19 studies, 9072 cases and 7487 controls), e89A/G (7 studies, 2237 cases and 1621 controls), 96T/C (three studies, 497
cases and 502 controls) polymorphism and RA risk in the overall population. After stratifying by ethnicity, the results also showed that these polymorphisms were not associated with RA risk in any of the subgroups. Heterogeneity and Publication Bias Heterogeneity of the included studies regarding each polymorphism is presented in Table 2. Heterogeneity was found among the PADI4e94G/A. e92C/G, e104C/T, e89A/G and e90C/T polymorphisms in the overall group and some subgroup study subjects. Thus, these meta-analyses were performed using the random-effects model, another meta-analysis was performed using the fixed-effects model.
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Meta-analysis of PADI4 Gene Polymorphisms and RA
Figure 3. Odds ratios and 95% confidence intervals for individual studies and pooled data for the association between the C vs. T allele of the PADI4e90C/T polymorphism and rheumatoid arthritis.
To explore potential sources of heterogeneity in this meta-analysis, meta-regression analysis was performed. Confounding factors included sample size, ethnicity, publication year, and genotyping method. The results showed that these potential factors were all probably not the major sources of heterogeneity (all p value for regression O0.05). The funnel plot and Egger’s test were performed to access publication bias. In the present study, no publication bias was found (Table 2). Discussion Although the multifactorial nature of RA is well known, genetic factors are considered to be strong determinants of these diseases, thus encouraging researchers to search for the responsible genes. PADI4 has been implicated in the pathogenesis, activity and severity of RA (45,48). Recently, investigations on the relationship between PADI4 gene polymorphisms and RA have been extensively performed in different populations. However, results of individual studies were inconclusive. Takata et al. (16)
observed that PADI4e94 was modestly associated with RA. Cheng et al. (34) also suggested that the functional single-nucleotide polymorphism (SNP) PADI4e94G/A variant allele is associated with RA development. In contrast, Chen et al. (15) discovered no significant difference in the allele frequency of PADI4e94G/A between patients with RA and controls in Chinese. To comprehensively analyze these associations between PADI4 gene polymorphisms and RA susceptibility, a meta-analysis was performed. Compared with the previous meta-analysis (38,39), the current study involved more research (28 articles, 34 studies). This is the first meta-analysis to investigate the association between the PADI4_96T/C polymorphism and RA susceptibility. This is also the first meta-analysis to include an African population and three PADI4 gene loci (PADI4_94, PADI4_92, PADI4_96), Latin American population and three PADI4 gene loci (PADI4_92, PADI4_89, PADI4_90). In addition, we excluded studies in which HWE was absent in the controls. As several studies have reported significant associations between genetic polymorphisms and diseases
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when the genotype distribution of the control population deviated from HWE, deviation from HWE in the control population might imply potential selection biases of controls or genotype errors. Therefore, our meta-analysis might draw a more reliable conclusion. The overall results demonstrated that PADI4e94G/A polymorphism was significantly associated with RA susceptibility. However, we failed to detect an association between PADI4e92C/G, PADI4e104C/T, PADI4e89A/G, PADI4e90C/T and PADI4e96T/C polymorphisms and RA risk. In the present study, we also performed subgroup analyses by ethnicity for these polymorphisms. Our results revealed that the PADI4e94G/A polymorphism was associated with RA in Asians, but not in Europeans. These results were very different from those observed by Iwamoto et al. (38) and Hou et al. (39) in the previous meta-analysis. Furthermore, in this meta-analysis we found the PADI4e92C/G polymorphism was associated with RA in Africans, whereas the PADI4e90C/T polymorphism was associated with RA in Latin Americans. However, this might not be reliable because only one published article in each of the two groups was included in the present study. Therefore, additional large sample size case-control studies should be performed in these two groups. Some potential limitations of this meta-analysis should be acknowledged. First, this study could not analyze the potential gene-environment interactions and gene susceptibility haplotypes due to limited data, such as data on environmental risk factors and genotypes. Second, our literature search was dependent on English and Chinese; therefore, language bias might be considered. Third, although we used random-effect models to pool ORs if significant heterogeneities between studies were observed in comparisons, heterogeneities and confounding factors still exist and may distort the meta-analysis. Fourth, different genotyping methods and disease status might affect the interpretation of the data of included studies. Finally, meta-analysis remains a retrospective research subject to the methodological deficiencies of the included studies. In conclusion, this updated meta-analysis demonstrates that PADI4e94G might be risk alleles for RA susceptibility, especially in Asians. It has also been detected that PADI4e92C/G polymorphism confers susceptibility to RA in Africans and the PADI4e90C/T polymorphism was associated with RA in Latin Americans. However, large-scale studies including more ethnic groups with careful matching between cases and controls should be considered to further explore the relationship between polymorphisms in the PADI4 genes and the pathogenesis of RA. Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (81271759).
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