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. 2016 Jan 11;24(2):444–449. doi: 10.1016/j.sjbs.2016.01.013

Promoter polymorphism (−590, T/C) of interleukin 4 (IL4) gene is associated with rheumatoid arthritis: An updated meta-analysis

Hyun Kyung Park a,1, Su Kang Kim b,1, Hae Yong Kweon c, Kwan Gill Lee c, Mariadhas Valan Arasu d, Young Ock Kim e,⁎
PMCID: PMC5272927  PMID: 28149185

Abstract

Rheumatoid arthritis (RA) is a chronic disease. It causes chronic inflammation of the joint. Recent studies suggested that interleukin 4 (IL4) contributes to susceptibility and severity of rheumatoid arthritis (RA). Especially, it was reported that promoter polymorphism (−590, T/C) of IL4 gene has been associated with susceptibility of RA. The aim of present study was to investigate whether the promoter polymorphism (−590, T/C) of IL4 gene is associated with the susceptibility of RA using meta-analysis. And in order to perform meta-analysis, comprehensive meta analysis program was used. Genetic models (co-dominant, dominant, recessive, and allele) were used to determine odds ratios (ORs), 95% confidence intervals (CIs), and P values. Nine case-control studies with case and control design were included in this meta-analysis. Overall, meta-analysis revealed a strong association with susceptibility of RA [OR = 1.303, 95% CI = 1.093–1.554, P = 0.003 in allele model (C vs. T); OR = 1.247, 95% CI = 1.054–1.474, P = 0.010 in dominant model (CC vs. CT + TT); OR = 2.148, 95% CI = 1.263–3.651, P = 0.005 in recessive model (CC + CT vs. TT)]. Our data demonstrated that promoter polymorphism (−590, T/C) of IL4 gene may be contributed to susceptibility of RA. However, more studies with a larger sample size are needed to provide more precise evidence.

Keywords: Interleukin 4, Polymorphism, Rheumatoid arthritis, Association study, Meta-analysis

1. Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory disorder and the most common inflammatory arthritis (Lee and Weinblatt, 2001, Antonisamy et al., 2015). The incidence of RA in 2008 was estimated to be 42/100,000 in South Korea (Sung et al., 2013). And the annual incidence in Norway was 28.7/100,000 (Riise et al., 2000) and 44.6/100,000 in Rochester, Minnesota (Doran et al., 2002).

RA is the most common autoimmune disease. The adaptive T-cell response interactions with environmental factors such as smoking lead to a systemic autoantibody response and it results in the synovial inflammatory process (Pablos and Canete, 2013). In these inflammatory responses, many previous studies investigated the role of genetic factors. HLA has been regarded as an important genetic factor in RA risk (Ollier and MacGregor, 1995). IL27 gene polymorphism was associated with susceptibility of RA in Chinese (Yan et al., 2015). Recent meta-analysis showed the association between CCR6 polymorphism and RA (Cheng et al., 2015).

IL4 gene is located at 5q31.1 and encodes interleukin 4 (http://www.ncbi.nlm.nih.gov). IL4 improves anti-inflammatory effect and suppresses several pro-inflammatory cytokines and systemic IL4 treatment protects the cartilage and bone destruction in established murine type II collagen-induced arthritis (Joosten et al., 1999). Also, IL4 could be used for the treatment of RA in association with anti-TNF alpha or anti-IL1 beta (Meyer, 2003). Genetic polymorphism of IL4 also has an association with RA. IL4 promoter polymorphism may be a genetic risk factor for RA severity (Pawlik et al., 2005). Previous study also suggested that the promoter polymorphism may be helpful for assessing RA severity (joint erosion and anti-CCP) and TT genotype of polymorphism (−590) showed a significant decrease of IL4 level in serum (Moreno et al., 2007).

Though the roles of IL4 polymorphisms in RA have been reported in Chinese (Li et al., 2014) or White participants, the results has been controversial. In this study, we performed a meta-analysis on all eligible case-control studies to clarify the association between IL4 polymorphism (−590) and susceptibility to RA.

2. Materials and methods

2.1. Search strategy and data extraction

We firstly found the meta-analysis studies between IL4-590 polymorphism and RA. And electronic database including pubmed, embase, google of scholar, and Korean Studies Information Service System (KISS) were investigated up to June 2015. In order to select eligible studies about IL4-590 polymorphism and RA. The keywords to find eligible studies were used: “interleukin 4”, “IL4“, or “cytokine”, AND “polymorphism” or “SNP” AND “−590” or “rs2243250“ AND “RA”. The data of first author’s name, year of publication, country, sample size of RA and control, genotype frequencies of IL4-590 polymorphism in RA and control were extracted from the final selected studies.

2.2. Inclusion criteria

Studies were included if they met the following criteria: (1) evaluated the association between the IL4 polymorphism (−590, T/C) and RA; (2) used a case-control study design; (3) contained sufficient published data for the estimation of an odds ratio (OR) with a 95% confidence interval (CI).

2.3. Statistical analysis

Hardy–Weinberg equilibrium (HWE) in the control group of include studies was evaluated by the Chi-square test. Meta-analysis and sensitivity analysis were used by the Comprehensive Meta-analysis software (Corporation, NJ, USA). The pooled p value, OR, and 95% CI were used to assess the strength of association between risk of RA and IL4-590 polymorphism (Kim et al., 2013, Seok et al., 2014). The meta-analysis was performed while omitting each study one at a time to examine the influence of each study on the pooled OR. In order to assess heterogeneity among the studies, a χ2-test-based Q statistic test and I squared test were done. The random-effects Mantel–Haenszel method was adopted if the result of the Q test was P < 0.05 or I squared value was >50%, which indicated the statistically significant heterogeneity between the studies. Otherwise, the fixed-effects Mantel–Haenszel method was adopted. And Begg’s funnel plot and Egger’s test were performed to evaluate publication bias. For sensitivity analysis, the meta-analysis was performed subtracting each study to examine the influence of each study over and over again. The P < 0.05 was regarded as statistically significant.

3. Results

The present study performed the meta-analysis to assess relationship between promoter polymorphism (−590, T/C) of IL4 gene and susceptibility of RA. Firstly, searching was conducted to find related studies from electronic databases according to search strategy. Eleven case and control studies about promoter polymorphism (−590, T/C) of IL4 gene polymorphism (Ser326Cys) and susceptibility of RA were searched (Canet et al., 2015, Cantagrel et al., 1999, Emonts et al., 2011, Hussein et al., 2013, Li et al., 2014, Nunez et al., 2008, Moreno et al., 2007, Pawlik et al., 2005, Plenge et al., 2005, Trajkov et al., 2009). Among these studies, six studies (Cantagrel et al., 1999, Pawlik et al., 2005, Moreno et al., 2007, Nunez et al., 2008, Trajkov et al., 2009, Hussein et al., 2013) were analyzed by meta-analysis in 2013 (Song et al., 2013). However, there was an error in data by the meta-analysis in 2013. Song et al., 2013 reported results of meta-analysis between promoter polymorphism (−590, T/C) of IL4 gene and susceptibility of RA. They included the data from the study (Cantagrel et al., 1999) in the meta-analysis They summarized that the genotype frequencies (C/C:C/T:T/T) of promoter polymorphism (−590, T/C) of IL4 gene in the control group were 32:36:0, but original data of the study (Cantagrel et al., 1999) is 82:36:0. In meta-analysis between specific polymorphisms and susceptibility of diseases, it was important to search eligible studies and extract exact data. So, this updated meta-analysis was performed.

Table 1 shows characteristics of eligible studies included in the meta-analysis. The first author’s name, year of publication, country, sample size, and genotype frequencies of IL4-590 polymorphism in RA patients and controls were extracted. Among eleven studies, studies by Trajkov et al., 2009, Canet et al., 2015 were excluded in the meta-analysis because HWEs of genotype distribution of IL4-590 polymorphism in the control group was p < 0.05. Table 2 and Fig. 1 presents the results of meta-analysis between IL4-590 polymorphism and susceptibility of RA in nine studies. In all models, IL4-590 polymorphism revealed the significant association with susceptibility of RA (random model, OR = 1.303, 95% CI = 1.093–1.554, P = 0.003 in allele; random model, OR = 1.247, 95% CI = 1.054–1.474, P = 0.010 in dominant; random model, OR = 2.148, 95% CI = 1.263–3.651, P = 0.005 in recessive; Fixed model, OR = 1.128, 95% CI = 1.025–1.241, P = 0.014 in codominant 1; Random model, OR = 2.272, 95% CI = 1.313–3.931, P = 0.003 in codominant 2). Sensitivity analysis confirmed the stability of the results of meta-analysis (data not shown) and no publication bias was found in the present meta-analysis. These results indicate that promoter polymorphism (−590, T/C) of IL4 gene polymorphism is related to susceptibility of RA (Table 2 and Fig. 1).

Table 1.

Characteristics of eligible studies included in the meta-analysis.

Study Country RA/Control (n) Genotyping method RA
 Control
 RA
 Control
 HWE in control
C/C C/T T/T C/C C/T T/T C T C T
Trajkov et al. (2009) Macedonia 85/286 Sequencing 47 37 1 95 187 4 131 39 377 195 <0.001
Nuñez et al. (2008) Spain 599/540 TaqMan 398 179 22 375 155 10 975 223 905 175 0.185
Moreno et al. (2007) Colombian 102/102 PCR-RFLP 39 48 15 49 48 5 126 78 146 58 0.11
Pawlik et al. (2005) Poland 94/102 PCR-RFLP 62 28 4 74 26 2 152 36 174 30 0.87
Plenge et al. (2005) Sweden 1503/875 Sequenom 940 507 56 584 253 38 2387 619 1421 329 0.12
Plenge et al. (2005) North America 835/847 Sequenom 594 219 22 571 254 22 1407 263 1396 298 0.38
Cantagrel et al. (1999) France 107/68 PCR-RFLP 63 41 3 82 36 0 167 47 200 36 0.05
Emonts et al. (2011) Netherland 372/460 Sequencing 267 91 14 339 112 9 625 119 790 130 0.94
Hussein et al. (2013) Egypt 172/172 PCR-RFLP 96 56 20 123 46 3 248 96 292 52 0.58
Li et al. (2014) China 752/798 PCR-RFLP 481 218 53 575 207 16 1180 324 1357 239 0.60
Canet et al. (2015) Spain 1239/1229 KASPar 859 325 34 863 275 34 2043 393 2001 343 0.037
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RA = rheumatoid arthritis, n = number of subjects.

Bold number indicates significant difference.

Table 2.

Overall analysis between IL4-590 polymorphism and susceptibility of RA in nine studies.

Genetic comparison Association
 Heterogeneity
 Model Publication bias
OR (95% CI) P P I2 Egger’s test
C vs. T 1.303 (1.093–1.554) 0.003 <0.001 75.46 Random 0.18
C/C vs. C/T + T/T 1.247 (1.054–1.474) 0.010 0.006 62.75 Random 0.22
C/C + C/T vs. T/T 2.148 (1.263–3.651) 0.005 <0.001 72.26 Random 0.09
C/C vs. C/T 1.128 (1.025–1.241) 0.014 0.100 40.28 Fixed 0.37
C/C vs. T/T 2.272 (1.313–3.931) 0.003 <0.001 73.55 Random 0.10
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Rheumatoid arthritis (RA), odds ratio (OR), confidence interval (CI), number of subjects (n).

Bold numbers indicate significant association with RA.

Figure 1.

Figure 1

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Odds ratio and 95% CI of individual and pooled data for the IL4 polymorphism (−590) and susceptibility of RA. A: C allele vs. T allele; B: C/C genotype vs. C/T genotype + T/T genotype; C: C/C genotype + C/T genotype vs. T/T genotype.

4. Discussion

Many factors such as gene, cytokine, inflammatory mediators, adhesion molecules, and so on involve in the pathophysiology of RA. Among them, many genetic factors have been identified due to advances in genetic methods (Lee and Weinblatt, 2001). In this study, we focused on the genetic factor of RA and carried out meta-analysis to investigate the relation between IL4 polymorphism and the risk of developing RA.

In the present study, we could find significant associations in allele, dominant, and recessive models. The results of this meta-analysis are consistent with the results of a previous meta-analysis (Canet et al., 2015). Among these, only the study by Li et al. (2014) involves Asian population (Chinese). According to NCBI database, genotype frequency in Chinese is 0.023 (C/C), 0.395 (C/T), and 0.581 (T/T) and allele frequency in Chinese is 0.221 (C) and 0.779 (T). On the other hand, genotype and allele frequencies in White are definitely different. According to NCBI database, genotype frequency in European is 0.743 (C/C), 0.239 (C/T), and 0.018 (T/T) and allele frequency in Chinese is 0.863 (C) and 0.137 (T). As shown in Table 1, genotype and allele frequencies in previous studies are similar to those in NCBI database. Interestingly, the genotypes and allele frequencies in 2014 by Li et al. (2014) are similar to those of European rather than those of Asian according to NCBI database. Previous study reported that the incidence and prevalence of RA showed different trends according to ethnicity. In Korea, the prevalence of RA in 2008 was estimated to be 0.27% (Sung et al., 2013). One study on rural African had found only 14 cases of RA in about 520,000. The prevalence of RA was 0.0026% (Brighton et al., 1988). In contrast, the prevalence of RA in a Chippewa Band (American Indian) reached to 5.3–6.8% (Harvey et al., 1981). A study in Norway reported that the prevalence of RA was 0.47% in 1994 (Riise et al., 2000). In United Kingdom, the prevalence of RA is 1.16% in women and 0.44% in men (Symmons et al., 2002). The prevalence of RA in the urbanized Chinese of Hong Kong was 0.35% (Lau et al., 1993). Thus, previous studies showed the significant geographic variations of RA occurrence and difference of prevalence according to ethnicity. These results suggest an association of RA with ethnicity and genetic factors.

5. Conclusion

In conclusion, our meta-analysis study showed that IL4 polymorphism was associated with RA. However, the limitation of our study is that there was not enough data on other ethnicities. We could not find the studies on African population and the number of studies on Asian was only one. In spite of these limitation, our meta-analysis provided evidence of the association between IL4 polymorphism and risk of RA. It is well known that early diagnosis and treatment of RA could lead to favorable outcomes. Therefore, early diagnosis and preventive treatment by detecting the susceptibility to RA in gene level would play a major role in improving the prognosis of RA. Many previous association studies revealed the association between IL4 polymorphism and RA and our present meta-analysis strengthened the relationship. If further studies will be performed in more population, promoter polymorphism (−590, T/C) of IL4 gene could be a useful marker for the early diagnosis and treatment of RA.

Author disclosure statement

No competing financial interests exist.

Acknowledgment

This work was supported by a Grant from Kyung Hee University in 2010 (KHU-20101896).

Footnotes

Peer review under responsibility of King Saud University.

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