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Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis
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ORIGINAL ARTICLE
Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis Qi-Fei Liu 1, Yi Li 1, Qi-Hong Zhao , Zheng-Yu Wang , Shuang Hu , Chao-Qun Yang , Kui Ye , Li Li ∗ Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui Province 230601, China
Summary Objective: Association of Signal transducers and activators of transcription-4 (STAT4) gene polymorphism with susceptibility to inflammatory bowel disease have been investigated in a number of epidemiological studies, but the results are inclusive. The aim of this meta-analysis was to more precisely estimate the relationship. Methods: The databases of Pubmed and CBM updated to October, 2014 were retrieved. Randomor fixed-effect model was used to estimate odd radio (OR) and corresponding 95% confidence interval (95%CI) on the basis of heterogeneity. Results: Seven articles containing 2196 Crohn’s disease (CD) cases, 1588 ulcerative colitis (UC) cases and 4126 controls were identified. We detected a significant association between STAT4 rs7574865 polymorphism and IBD susceptibility in overall population (GG vs. GT + TT, OR = 0.855, 95% CI = 0.760—0.962, P = 0.009), but not in Caucasian and Asian population, respectively. No association was detected between rs7574865 polymorphism and CD susceptibility in overall, Asian and Caucasian population, respectively. Interestingly, a significant association was detected between rs7574865 with UC susceptibility in overall population (G vs. T, OR = 0.881, 95% CI = 0.798—0.972, P = 0.012; GG vs. GT + TT, OR = 0.788, 95% CI = 0.679—0.914, P = 0.002; GG vs. TT, OR = 0.683, 95% CI = 0.498—0.937, P = 0.018) and Caucasians (GG vs. GT + TT, OR = 0.833, 95% CI = 0.701—0.990, P = 0.038; GG + GT vs. TT, OR = 0.667, 95% CI = 0.456—0.975, P = 0.037; GG vs. TT, OR = 0.636, 95% CI = 0.433—0.934, P = 0.021), respectively, and a possible association was found in Asian population (GG vs. GT + TT, OR = 0.709, 95% CI = 0.503—0.998, P = 0.049).
∗ 1
Corresponding author. E-mail address: [email protected] (L. Li). These authors contributed equally to this work and should be considered co-first authors.
http://dx.doi.org/10.1016/j.clinre.2015.04.002 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Conclusions: STAT4 rs7574865 gene is IBD risk factor, and this gene polymorphism is associated with UC susceptibility, especially in Caucasians. To confirm these findings, further studies with more sample size are required for a definitive conclusion. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction Inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn’s disease (CD), are relapsing and chronic inflammatory disorders thought to be caused by complex interactions between genetic, environmental, and other processes involving immunoregulatory factors [1—3]. IBD is a major burden for health systems in Western countries, for prevalence studies, the UC estimates ranged from 4.9 to 505 per 100,000 in Europe, 4.9 to 168.3 per 100,000 in Asia and the Middle East and the CD estimates ranged from 0.6 to 322 per 100,000 in Europe, 0.88 to 67.9 per 100,000 in Asia and the Middle East [4]. Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified a considerable number of IBD susceptibility genes, such as NOD2, IL23R, ATG16L1 and IRGM [5—8]. However, the genetic polymorphisms located within these genes are not sufficient to adequately explain the pathogenesis of IBD or the variations in disease phenotypes. Thus, the identification of new IBD susceptibility and severity genes is currently an important challenge. Signal transducers and activators of transcription-4 (STAT4), a critical transcription factor transducing IL12-, IL-23-, and type 1 interferon-mediated signals into Th1 and Th17 differentiation, monocyte activation, and interferon-gamma production [9,10]. The requirement for STAT4-dependent cytokine regulation has well been replicated for the pathogenesis of autoimmune disease [11,12], such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and also IBD [13—15], highlighting a critical role for STAT4 in autoimmune diseases. STAT4 gene is located on chromosome 2q33 region of the human genome. Recently, STAT4 haplotype characterized by the rs7574865 polymorphism was reported to be significantly associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other autoimmune diseases such as Sjögren’s syndrome, type 1 diabetes, and systemic sclerosis [16—18]. Interestingly, a recent casecontrol study conducted in a Spanish population showed that the T allele of the STAT4 rs7574865 was associated with IBD [19], and this association has been replicated by Diaz-Gallo et al. [20] and Glas et al. [21], they reported that rs7574865 polymorphism was associated with colonic CD and early disease onset in Caucasians. However, there are also some other studies did not confirm these findings. Bouzid et al. [22] demonstrated that STAT4 rs7574865 SNP (P = 0.026;OR = 1.65, 95% CI = 1.06—2.58) exhibited a marginal association with UC but not with CD in the Tunisian population. Moon et al. [23] did not observe any correlation between haplotype patterns and disease susceptibility to UC or CD in Korean participants, and Zhu et al. [24] and Pang et al. [25] did not support that STAT4 variants
contribute to IBD susceptibility in the Chinese Han population. Controversial and inclusive results of previous studies may due to inadequate statistical power, racial and ethnic difference, and publication bias. Meta-analysis is a powerful tool for summarizing the results from different studies by producing a single estimate of the major effect with enhanced precision. Thus, in this meta-analysis, we explored whether the STAT4 rs7574865 polymorphism contributes to IBD susceptibility.
Materials and methods Literature search We conducted a literature search on articles that examined the association of the STAT4 rs7574865 gene polymorphism with IBD susceptibility using PubMed and CBM databases (up to October, 2014), and without language or region restriction. The key words as follows: (‘‘Signal transducers and activators of transcription-4’’ or ‘‘STAT4’’ or ‘‘rs7574865’’) and (‘‘polymorphism’’ or ‘‘polymorphisms’’ or ‘‘variant’’) and (‘‘Crohn’s disease’’ or ‘‘ulcerative colitis’’ or ‘‘inflammatory bowel disease’’). References in identified studies were also investigated to identify studies not indexed by PubMed and CBM citation database.
Inclusion and exclusion criteria Eligible studies should meet the following criterion: • it was a case-control study; • it addressed STAT4 rs7574865 polymorphism with IBD risk; • it provided the allele frequency or genotype distribution data; • it had enough information to estimate an odds ratio (OR) with 95% confidence interval (CI). Accordingly, we excluded the followings: • studies that contained overlapping data; • meeting abstracts and reviews; • genotype distribution of the control population was not in Hardy-Weinberg equilibrium (HWE).
Data extraction Two authors (Qi-Fei Liu and Yi Li) independently extracted data from all eligible studies. Discrepancies were resolved after discussion with our research team. The following data were collected from each study:
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Stat4 rs7574865 polymorphism and IBD
Figure 1
• • • • • • • •
3
The flow chart of the study selection process.
first author; year of publication; ethnicity of the population studied; genotyoing method; source of controls; total numbers of cases and controls; Hardy-Weinberg equilibrium and; distribution of genotypes and alleles in cases and controls, respectively.
Statistical analysis The strength of association between STAT4 rs7574865 and IBD risk was measured by ORs with 95% CIs. Meta-analyses were performed using the following: • • • •
allelic contrast; recessive models; dominant models and; homozygote contrast.
The heterogeneity between studies was evaluated by Cochrane’s Q-statistic as well as I2 -statistic, which was used to quantify the effect of heterogeneity (I2 = 100% (Q—df)/Q)
[26]. I2 values of 25, 50, and 75% were nominally considered low, moderate, and high estimates, respectively. When the P-value of heterogeneity tests was no more than 0.1 (P < 0.1), we used a random-effects model. Otherwise, fixedeffects model were used. Sensitivity analysis was also performed by removing one study at a time to calculate the overall homogeneity and size effect. Publication bias was investigated by funnel plot and Egger’s linear regression test (P < 0.05 was considered representative of statistically significant publication bias) [27]. All analysis were performed using the Software State version 11.0 (StataCorp LP, College Station, TX, USA). All the P-values were two sided.
Results Study characteristics Based on our search criteria, a total of seven eligible studies concerning the STAT4 rs7574865 polymorphism and IBD risk were included in the final meta-analysis [19—25], comprising 2196 CD cases, 1588 UC cases and 4126 controls. The flow chart of the study selection process is shown in Fig. 1. The diagnosis of all patients included in these seven studies
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Q.-F. Liu et al. Table 1 Characteristics of studies investigating the association of STAT4 rs7574865 gene polymorphism with Crohn’s disease or ulcerative colitis. Author
Year
Population
Ethnicity
Source of controls
Genotyping method
Type
Sample size Case
HWE
Control
Zhu H
2013
Chinese
Asian
HB
QIAamp
IBD CD UC
388 232 56
274 274 274
Y (P = 0.16)
Moon CM
2010
Korean
Asian
HB
PCR
IBD CD UC
428 182 246
229 229 229
Y
Martínez A
2008
Spanish
Caucasian
HB
TaqMan
IBD CD UC
674 322 352
716 716 716
Y (P > 0.05)
Glas J
2010
German
Caucasian
HB
PCR
IBD CD UC
1321 857 464
1383 1383 1383
Y
Diaz-Gallo LM
2010
Spanish
Caucasian
HB
Taqman
IBD CD UC
900 498 402
1296 1296 1296
Y
Bouzid D
2011
Tunisian
African
HB
Sequenom
IBD CD UC
107 39 68
162 162 162
Y (P = 0.549)
Pang Z
2011
Chinese
Asian
NA
PCR
IBD CD
66 66
66 66
Y (P > 0.05)
3884 2196 1588
4126 4126 4060
Total IBD CD UC
HB: hospital basic case-control study; PCR: polymerase chain reaction; NA: not available; IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; Y: genotype of controls meet Hardy-Weinberg equilibrium.
was based on standard clinical, radiographic, endoscopic, and histopathological criteria [6]. There were seven studies involving CD patients and six studies involving UC patients. There were three studies of Caucasians, three studies of Asians, and one study of Africans. Meanwhile, six studies published in English language, and one study published in Chinese. Genotypes in control group for all studies were consistent with HWE (P > 0.05). Main characteristics of the included studies are shown in Table 1, and allele or genotype distributions of each study are shown in Table 2.
Quantitative synthesis The results of the association between STAT4 rs7574865 polymorphism and IBD risk, and the heterogeneity test are shown in Table 3 and Fig. 2, respectively. Meta-analysis of all studies showed a significant association between rs7574865 and IBD susceptibility in all subjects in dominant model (GG vs. GT + TT, OR = 0.855, 95% CI = 0.760—0.962, P = 0.009), but not in allelic, recessive and homozygote models. Stratification by ethnicity, no association was found in Caucasians and Asians in all models.
Stratification by disease type, no association was found between rs7574865 polymorphism and CD susceptibility in overall population, in Caucasians and in Asians in all models. But only one study demonstrated a possible association in African population in allelic model (G vs. T, OR = 1.167, 95% CI = 1.003—1.357, P = 0.045). The details are shown in Table 4 and Fig. 3. Interestingly, we detected a significant association between rs7574865 polymorphism and UC in overall population (allelic model G vs. T, OR = 0.881, 95% CI = 0.798—0.972, P = 0.012; dominant model GG vs. GT + TT, OR = 0.788, 95% CI = 0.679—0.914, P = 0.002; homozygote model GG vs. TT, OR = 0.683, 95% CI = 0.498—0.937, P = 0.018). Stratification by ethnicity, an association was detected in Caucasians (dominant model GG vs. GT + TT, OR = 0.833, 95% CI = 0.701—0.990, P = 0.038; recessive model GG + GT vs. TT, OR = 0.667, 95% CI = 0.456—0.975, P = 0.037; homozygote model GG vs. TT, OR = 0.636, 95% CI = 0.433—0.935, P = 0.021), and a possible association was detected in Asians in dominant model (GG vs. GT + TT, OR = 0.709, 95% CI = 0.503—0.998, P = 0.049). The details are shown in Table 4 and Fig. 4.
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Stat4 rs7574865 polymorphism and IBD Table 2
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Allele and genotype information of IBD, CD, UC cases and controls.
Author
Type
Case
Control
G
T
GG
GT
TT
G
T
GG
GT
TT
Zhu H
CD UC IBD
220 51 271
236 61 297
19 4 23
182 43 225
27 9 36
269 269 269
273 273 273
39 39 39
191 191 191
41 41 41
Moon CM
CD UC IBD
254 325 579
110 167 277
89 97 186
76 131 207
17 18 35
312 312 312
146 146 146
106 106 106
100 100 100
23 23 23
Martínez A
CD UC IBD
494 541 1035
150 163 313
191 209 400
112 123 235
19 20 39
1160 1160 1160
272 272 272
470 470 470
220 220 220
26 26 26
Diaz-Gallo LM
CD UC IBD
807 619 1426
189 185 374
320 241 561
167 137 304
11 24 35
2054 2054 2054
538 538 538
813 813 813
428 428 428
55 55 55
Bouzid D
CD UC IBD
60 103 163
18 33 51
23 39 62
14 25 39
2 4 6
272 272 272
52 52 52
113 113 113
46 46 46
3 3 3
Pang Z
CD IBD
45 45
87 87
9 9
27 27
30 30
41 41
91 91
6 6
29 29
31 31
Glas J
CD UC IBD
1388 729 2117
326 199 525
NA NA NA
NA NA NA
NA NA NA
2171 2171 2171
595 595 595
NA NA NA
NA NA NA
NA NA NA
IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis.
Heterogeneity and publication bias No between-study heterogeneity was found in metaanalyses of the rs7574865 polymorphisms UC susceptibility in the overall population, in Caucasians, or in Asians. So fixed-effect models were used to calculate the relationship. However, obvious heterogeneity was detected in rs7574865
Table 3
polymorphism with IBD and CD susceptibility, after stratification by ethnicity, the heterogeneity still exists in some comparisons. So random-effect models were used to assess the relationship (Tables 3 and 4). The results of Egger’s linear regression test are shown in Tables 3 and 4. It was shown that there was no publication bias except for the comparisons of G vs. T in Caucasian population of rs7574865
Meta-analysis of the association between the STAT4 rs7574865 polymorphism and inflammatory bowel disease.
Comparison
G vs. T Allelic model
GG vs. GT + TT Dominant model GG + GT vs. TT Recessive model GG vs. TT Homozygote model
Ethnicity
Over all Caucasian Asian African Over all Caucasian Asian Over all Caucasian Asian Over all Caucasian Asian
No. of study
7 3 3 1 6 2 3 6 2 3 6 2 3
Test of association
Model
OR
95% CI
P-value
0.968 0.986 0.969 1.105 0.855 0.890 0.809 0.983 0.857 0.198 0.849 0.825 0.983
0.898—1.043 0.904—1.075 0.825—1.137 0.969—1.261 0.760—0.962 0.777—1.020 0.620—1.056 0.785—1.231 0.619—1.186 0.869—1.651 0.661—1.092 0.594—1.145 0.652—1.481
0.395 0.743 0.696 0.137 0.009 0.095 0.120 0.879 0.352 0.271 0.203 0.249 0.935
R R F NA R R F F R F F R F
Test of heterogeneity P-value
I2 (%)
0.023 0.008 0.754 NA 0.084 0.077 0.121 0.177 0.089 0.926 0.127 0.060 0.351
59.0 79.1 0.0 NA 48.6 67.9 52.6 34.5 65.5 0.0 41.8 71.8 4.5
Egger’s (P-value)
0.333 0.029 0.249 NA 0.507 NA 0.914 0.293 NA 0.349 0.605 NA 0.781
vs.: versus; F: fixed-effects model; NA: not available; OR: odds ratio; CI: confidence interval. Significant P-values (< 0.05) are in bold.
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
CD
Comparison
G vs. T Allelic model
GG + GT vs. TT Recessive model GG vs. TT Homozygote model UC
G vs. T Allelic model
GG vs. GT + TT Dominant model GG + GT vs. TT Recessive model GG vs. TT Homozygote Model
No. of study
Test of association OR
95%CI
Model P-value
Test of heterogeneity
Egger’s (P-value)
2
P-value
I (%)
Over all Caucasian Asian African Over all Caucasian Asian Over all Caucasian Asian Over all Caucasian Asian
7 3 3 1 6 2 3 6 2 3 6 2 3
1.017 1.016 1.032 1.167 0.922 0.939 0.922 1.132 1.113 1.183 1.020 1.080 1.009
0.924—1.120 0.850—1.216 0.919—1.159 1.003—1.357 0.798—1.066 0.794—1.111 0.679—1.251 0.865—1.482 0.725—1.708 0.833—1.679 0.748—1.390 0.701—1.663 0.640—1.592
0.727 0.860 0.597 0.045 0.273 0.462 0.602 0.367 0.626 0.348 0.901 0.727 0.968
R F R NA R R R F R F R R F
0.076 0.706 0.013 NA 0.082 0.057 0.080 0.127 0.009 0.840 0.069 0.006 0.512
47.5 0.0 76.8 NA 48.9 72.5 60.5 41.8 85.4 0.0 51.1 86.9 0.0
0.457 0.422 0.291 NA 0.605 NA 0.995 0.471 NA 0.035 0.764 NA 0.596
Over all Caucasian Asian African Over all Caucasian Asian Over all Caucasian Asian Over all Caucasian Asian
6 3 2 1 5 2 2 5 2 2 5 2 2
0.881 0.898 0.891 1.004 0.788 0.833 0.709 0.798 0.667 1.198 0.683 0.636 0.941
0.798—0.972 0.802—1.005 0.711—1.117 0.838—1.203 0.679—0.914 0.701—0.990 0.503—0.998 0.593—1.074 0.456—0.975 0.725—1.980 0.498—0.937 0.433—0.934 0.524—1.688
0.012 0.061 0.317 0.966 0.002 0.038 0.049 0.137 0.037 0.482 0.018 0.021 0.838
F F F NA F F F F F F F F F
0.292 0.193 0.777 NA 0.501 0.397 0.384 0.239 0.781 0.420 0.345 0.687 0.207
18.7 39.2 0.0 NA 0.0 0.0 0.0 27.3 0.0 0.0 10.7 0.0 37.1
0.164 0.239 NA NA 0.032 NA NA 0.643 NA NA 0.362 NA NA
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GG vs. GT + TT Dominant model
Ethnicity
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Disease
Meta-analysis of the association between the STAT4 rs7574865 polymorphism and Crohn’s disease and ulcerative colitis.
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vs.: versus; R: random-effects model; F: fixed-effects model; NA: not available; OR: odds ratio; CI: confidence interval. Significant P-values (< 0.05) are in bold.
Q.-F. Liu et al.
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
Table 4
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Stat4 rs7574865 polymorphism and IBD
Figure 2 disease.
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Forest plots for the meta-analysis of association between STAT4 rs7574865 polymorphism and inflammatory bowel
with IBD susceptibility, GG + GT vs. TT in Asian population of rs7574865 with CD susceptibility and GG vs. GT + TT in overall population of rs7574865 with UC susceptibility.
Sensitivity analysis To determine the stability of the results of this metaanalysis, one-way sensitivity analyses were performed by sequentially excluding individual studies. The pooled ORs of the rs7574865 polymorphism and IBD, CD or UC were not influenced by the results of any individual study, indicating the stability of the results (data not shown).
Discussion It is well recognized that there is individual susceptibility to IBD even with the same environmental exposure. Host factors, including polymorphisms of genes involved in IBD, may have accounted for this difference. Therefore, genetic factors are considered to be strong disease determinants, and this has encouraged researchers to search for the responsible genes. Recently, accumulating evidence indicates that STAT4 is a pathogenic factor in IBD, both in animal models [28,29] and in humans [30]. STAT4 expression is very low
in resting T cells and is upregulated by the stimulation of TCR in response to IL-12. Constitutive STAT4 activation was observed in the mucosa from UC patients and in intestinal T cells of CD patients [31]. Kaplan et al. [32] and Jacob et al. [33] studied in STAT4-knockout and transgenic mice have demonstrated the critical role of STAT4 in immune responses to inflammatory diseases. In addition, STAT4 is required for the signal transduction of various pro-inflammatory cytokines highlights an important role of STAT4 in the pathogenesis of autoimmune diseases, including IBD. In the past years, an increasing number of studies mainly conducted in Caucasians or Asians to assess the association of STAT4 gene polymorphism with IBD susceptibility, but these studies have not reached a consistent result. The main reason for this discrepancy may due to the small sample size have insufficient statistical power to detect a weak association in some negative studies. So it is pressed for a meta-analysis to summarize the individual study for producing a pooled result. The present meta-analysis examined the association of STAT4 rs7574865 gene to IBD susceptibility containing 3784 IBD patients and 4126 controls. Our results reveal a significant association of the SNP rs7574865 in the STAT4 gene with IBD susceptibility in overall population, which raises the possibility that STAT4 is a susceptibility genetic factor for
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Figure 3
Forest plots for the meta-analysis of association between STAT4 rs7574865 polymorphism and Crohn’s disease.
this complex disease. However, after we stratified by ethnicity, this association was disappeared in Asian population and Caucasian population, it is possible that stratification make sample size decreasing, so we have insufficient statistical power to detected a weak association. We further stratification by disease type, we detected a significant association of STAT4 rs7574865 gene polymorphism with UC susceptibility in overall population and Caucasian population, and a possible association was found in Asian population (P = 0.049). For this possible association, it’s may a false-positive result producing by various bias or a real positive result, we should interpret with cautious and further study with more sample size and adequate statistical power is needed to clarify this possible association. In addition, we failed to detect any association of STAT4 rs7574865 polymorphism with CD susceptibility in overall population, Caucasian population and Asian population, but a possible association was detected in African population (P = 0.045). This possible association was result from only one study, so we are not sure rs7574865 is a CD susceptibility risk factor in Africans, further studies with more sample size are needed for a definitive conclusion. Indeed, CD and UC share many characteristics, but some clinical features also distinguish them. CD and UC likely share some genetic susceptibility loci but differ at others [34]. In this respect, a number of genetic loci, such as the ATG16L1, IRGM, MIF, IL23R, and IL12B genes polymorphisms
associated with both diseases have been described. Meanwhile, the ECM1, ARPC2, and IL-10 genes as well as regions on chromosomes 1p36, 2q24-37, and 12q15 are mainly associated with UC. However, the NOD2 gene, which is strongly associated with CD, is not a risk factor for UC susceptibility [2,34]. These differences may be caused by pleiotropic effects of specific genes on a common polygenic and multifactor background. The distinct influence of the STAT4 gene on IBD risk observed in our study provides an example of the differences in genetic background between these two intestinal inflammatory disorders [20]. The etiology of IBD, of which UC and BD are the two most prevailing entities, is unknown. However, IBD is characterized by an imbalanced synthesis of pro-inflammatory mediators of the inflamed intestine, and for more than a decade tumor necrosis factor-␣ (TNF-␣) has been a major target for monoclonal antibody therapy. However, TNF inhibitors are not useful for one third of all patients (i.e. ‘‘primary failures’’), and further one third lose effect over time (‘‘secondary failures’’). Therefore, other strategies have in later years been developed. Recently, STAT4 have been reported play a important roles in the pathogenesis of IBD. STAT4 represents a transcription factor transducing IL-12-, IL-23-, and type 1 interferon-mediated signals into Th1 and Th17 differentiation, monocyte activation, and interferon-gamma production. In our study, we clarify the
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Stat4 rs7574865 polymorphism and IBD
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Forest plots for the meta-analysis of association between STAT4 rs7574865 polymorphism and ulcerative colitis.
association between STAT4 rs7574865 polymorphism and IBD susceptibility, and found this SNP is associated with IBD and UC. Thus, STAT4 can be the diagnostic and therapeutic potential for IBD and UC. Drug development for IBD holds great promise, and patients as well as their treating physicians can be hopeful for the future. Similar as most other gene-related meta-analysis, some limitations of this study should be discussed. First, the number of studies included in the meta-analysis may be insufficient to detect slight associations, and the number of studies in some comparisons are relatively small, which may mean that our investigation was underpowered. Second, publication biases were detected in some comparisons, which may distort the results of this meta-analysis. Third, significant between-study heterogeneity was detected in IBD and CD studies. But it was not a major problem, because IBD and CD itself are heterogeneous. In conclusion, this meta-analysis provides evidence of the association between the STAT4 rs7574865 polymorphism and the risk of IBD, hinting that STAT4 rs7574865 polymorphism may play a role in IBD susceptibility. This meta-analysis also reveals STAT4 rs7574865 polymorphism is associated with UC susceptibility, especially in Caucasian population, but not associated with CD susceptibility in overall, Caucasian and Asian population, respectively. To confirm our findings, further studies with subtle study design based on larger sample size, case-control design, and stratification by ethnicity are still needed.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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ORIGINAL ARTICLE
Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis Qi-Fei Liu 1, Yi Li 1, Qi-Hong Zhao , Zheng-Yu Wang , Shuang Hu , Chao-Qun Yang , Kui Ye , Li Li ∗ Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui Province 230601, China
Summary Objective: Association of Signal transducers and activators of transcription-4 (STAT4) gene polymorphism with susceptibility to inflammatory bowel disease have been investigated in a number of epidemiological studies, but the results are inclusive. The aim of this meta-analysis was to more precisely estimate the relationship. Methods: The databases of Pubmed and CBM updated to October, 2014 were retrieved. Randomor fixed-effect model was used to estimate odd radio (OR) and corresponding 95% confidence interval (95%CI) on the basis of heterogeneity. Results: Seven articles containing 2196 Crohn’s disease (CD) cases, 1588 ulcerative colitis (UC) cases and 4126 controls were identified. We detected a significant association between STAT4 rs7574865 polymorphism and IBD susceptibility in overall population (GG vs. GT + TT, OR = 0.855, 95% CI = 0.760—0.962, P = 0.009), but not in Caucasian and Asian population, respectively. No association was detected between rs7574865 polymorphism and CD susceptibility in overall, Asian and Caucasian population, respectively. Interestingly, a significant association was detected between rs7574865 with UC susceptibility in overall population (G vs. T, OR = 0.881, 95% CI = 0.798—0.972, P = 0.012; GG vs. GT + TT, OR = 0.788, 95% CI = 0.679—0.914, P = 0.002; GG vs. TT, OR = 0.683, 95% CI = 0.498—0.937, P = 0.018) and Caucasians (GG vs. GT + TT, OR = 0.833, 95% CI = 0.701—0.990, P = 0.038; GG + GT vs. TT, OR = 0.667, 95% CI = 0.456—0.975, P = 0.037; GG vs. TT, OR = 0.636, 95% CI = 0.433—0.934, P = 0.021), respectively, and a possible association was found in Asian population (GG vs. GT + TT, OR = 0.709, 95% CI = 0.503—0.998, P = 0.049).
∗ 1
Corresponding author. E-mail address: [email protected] (L. Li). These authors contributed equally to this work and should be considered co-first authors.
http://dx.doi.org/10.1016/j.clinre.2015.04.002 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
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Conclusions: STAT4 rs7574865 gene is IBD risk factor, and this gene polymorphism is associated with UC susceptibility, especially in Caucasians. To confirm these findings, further studies with more sample size are required for a definitive conclusion. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction Inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn’s disease (CD), are relapsing and chronic inflammatory disorders thought to be caused by complex interactions between genetic, environmental, and other processes involving immunoregulatory factors [1—3]. IBD is a major burden for health systems in Western countries, for prevalence studies, the UC estimates ranged from 4.9 to 505 per 100,000 in Europe, 4.9 to 168.3 per 100,000 in Asia and the Middle East and the CD estimates ranged from 0.6 to 322 per 100,000 in Europe, 0.88 to 67.9 per 100,000 in Asia and the Middle East [4]. Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified a considerable number of IBD susceptibility genes, such as NOD2, IL23R, ATG16L1 and IRGM [5—8]. However, the genetic polymorphisms located within these genes are not sufficient to adequately explain the pathogenesis of IBD or the variations in disease phenotypes. Thus, the identification of new IBD susceptibility and severity genes is currently an important challenge. Signal transducers and activators of transcription-4 (STAT4), a critical transcription factor transducing IL12-, IL-23-, and type 1 interferon-mediated signals into Th1 and Th17 differentiation, monocyte activation, and interferon-gamma production [9,10]. The requirement for STAT4-dependent cytokine regulation has well been replicated for the pathogenesis of autoimmune disease [11,12], such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and also IBD [13—15], highlighting a critical role for STAT4 in autoimmune diseases. STAT4 gene is located on chromosome 2q33 region of the human genome. Recently, STAT4 haplotype characterized by the rs7574865 polymorphism was reported to be significantly associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other autoimmune diseases such as Sjögren’s syndrome, type 1 diabetes, and systemic sclerosis [16—18]. Interestingly, a recent casecontrol study conducted in a Spanish population showed that the T allele of the STAT4 rs7574865 was associated with IBD [19], and this association has been replicated by Diaz-Gallo et al. [20] and Glas et al. [21], they reported that rs7574865 polymorphism was associated with colonic CD and early disease onset in Caucasians. However, there are also some other studies did not confirm these findings. Bouzid et al. [22] demonstrated that STAT4 rs7574865 SNP (P = 0.026;OR = 1.65, 95% CI = 1.06—2.58) exhibited a marginal association with UC but not with CD in the Tunisian population. Moon et al. [23] did not observe any correlation between haplotype patterns and disease susceptibility to UC or CD in Korean participants, and Zhu et al. [24] and Pang et al. [25] did not support that STAT4 variants
contribute to IBD susceptibility in the Chinese Han population. Controversial and inclusive results of previous studies may due to inadequate statistical power, racial and ethnic difference, and publication bias. Meta-analysis is a powerful tool for summarizing the results from different studies by producing a single estimate of the major effect with enhanced precision. Thus, in this meta-analysis, we explored whether the STAT4 rs7574865 polymorphism contributes to IBD susceptibility.
Materials and methods Literature search We conducted a literature search on articles that examined the association of the STAT4 rs7574865 gene polymorphism with IBD susceptibility using PubMed and CBM databases (up to October, 2014), and without language or region restriction. The key words as follows: (‘‘Signal transducers and activators of transcription-4’’ or ‘‘STAT4’’ or ‘‘rs7574865’’) and (‘‘polymorphism’’ or ‘‘polymorphisms’’ or ‘‘variant’’) and (‘‘Crohn’s disease’’ or ‘‘ulcerative colitis’’ or ‘‘inflammatory bowel disease’’). References in identified studies were also investigated to identify studies not indexed by PubMed and CBM citation database.
Inclusion and exclusion criteria Eligible studies should meet the following criterion: • it was a case-control study; • it addressed STAT4 rs7574865 polymorphism with IBD risk; • it provided the allele frequency or genotype distribution data; • it had enough information to estimate an odds ratio (OR) with 95% confidence interval (CI). Accordingly, we excluded the followings: • studies that contained overlapping data; • meeting abstracts and reviews; • genotype distribution of the control population was not in Hardy-Weinberg equilibrium (HWE).
Data extraction Two authors (Qi-Fei Liu and Yi Li) independently extracted data from all eligible studies. Discrepancies were resolved after discussion with our research team. The following data were collected from each study:
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Stat4 rs7574865 polymorphism and IBD
Figure 1
• • • • • • • •
3
The flow chart of the study selection process.
first author; year of publication; ethnicity of the population studied; genotyoing method; source of controls; total numbers of cases and controls; Hardy-Weinberg equilibrium and; distribution of genotypes and alleles in cases and controls, respectively.
Statistical analysis The strength of association between STAT4 rs7574865 and IBD risk was measured by ORs with 95% CIs. Meta-analyses were performed using the following: • • • •
allelic contrast; recessive models; dominant models and; homozygote contrast.
The heterogeneity between studies was evaluated by Cochrane’s Q-statistic as well as I2 -statistic, which was used to quantify the effect of heterogeneity (I2 = 100% (Q—df)/Q)
[26]. I2 values of 25, 50, and 75% were nominally considered low, moderate, and high estimates, respectively. When the P-value of heterogeneity tests was no more than 0.1 (P < 0.1), we used a random-effects model. Otherwise, fixedeffects model were used. Sensitivity analysis was also performed by removing one study at a time to calculate the overall homogeneity and size effect. Publication bias was investigated by funnel plot and Egger’s linear regression test (P < 0.05 was considered representative of statistically significant publication bias) [27]. All analysis were performed using the Software State version 11.0 (StataCorp LP, College Station, TX, USA). All the P-values were two sided.
Results Study characteristics Based on our search criteria, a total of seven eligible studies concerning the STAT4 rs7574865 polymorphism and IBD risk were included in the final meta-analysis [19—25], comprising 2196 CD cases, 1588 UC cases and 4126 controls. The flow chart of the study selection process is shown in Fig. 1. The diagnosis of all patients included in these seven studies
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Q.-F. Liu et al. Table 1 Characteristics of studies investigating the association of STAT4 rs7574865 gene polymorphism with Crohn’s disease or ulcerative colitis. Author
Year
Population
Ethnicity
Source of controls
Genotyping method
Type
Sample size Case
HWE
Control
Zhu H
2013
Chinese
Asian
HB
QIAamp
IBD CD UC
388 232 56
274 274 274
Y (P = 0.16)
Moon CM
2010
Korean
Asian
HB
PCR
IBD CD UC
428 182 246
229 229 229
Y
Martínez A
2008
Spanish
Caucasian
HB
TaqMan
IBD CD UC
674 322 352
716 716 716
Y (P > 0.05)
Glas J
2010
German
Caucasian
HB
PCR
IBD CD UC
1321 857 464
1383 1383 1383
Y
Diaz-Gallo LM
2010
Spanish
Caucasian
HB
Taqman
IBD CD UC
900 498 402
1296 1296 1296
Y
Bouzid D
2011
Tunisian
African
HB
Sequenom
IBD CD UC
107 39 68
162 162 162
Y (P = 0.549)
Pang Z
2011
Chinese
Asian
NA
PCR
IBD CD
66 66
66 66
Y (P > 0.05)
3884 2196 1588
4126 4126 4060
Total IBD CD UC
HB: hospital basic case-control study; PCR: polymerase chain reaction; NA: not available; IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; Y: genotype of controls meet Hardy-Weinberg equilibrium.
was based on standard clinical, radiographic, endoscopic, and histopathological criteria [6]. There were seven studies involving CD patients and six studies involving UC patients. There were three studies of Caucasians, three studies of Asians, and one study of Africans. Meanwhile, six studies published in English language, and one study published in Chinese. Genotypes in control group for all studies were consistent with HWE (P > 0.05). Main characteristics of the included studies are shown in Table 1, and allele or genotype distributions of each study are shown in Table 2.
Quantitative synthesis The results of the association between STAT4 rs7574865 polymorphism and IBD risk, and the heterogeneity test are shown in Table 3 and Fig. 2, respectively. Meta-analysis of all studies showed a significant association between rs7574865 and IBD susceptibility in all subjects in dominant model (GG vs. GT + TT, OR = 0.855, 95% CI = 0.760—0.962, P = 0.009), but not in allelic, recessive and homozygote models. Stratification by ethnicity, no association was found in Caucasians and Asians in all models.
Stratification by disease type, no association was found between rs7574865 polymorphism and CD susceptibility in overall population, in Caucasians and in Asians in all models. But only one study demonstrated a possible association in African population in allelic model (G vs. T, OR = 1.167, 95% CI = 1.003—1.357, P = 0.045). The details are shown in Table 4 and Fig. 3. Interestingly, we detected a significant association between rs7574865 polymorphism and UC in overall population (allelic model G vs. T, OR = 0.881, 95% CI = 0.798—0.972, P = 0.012; dominant model GG vs. GT + TT, OR = 0.788, 95% CI = 0.679—0.914, P = 0.002; homozygote model GG vs. TT, OR = 0.683, 95% CI = 0.498—0.937, P = 0.018). Stratification by ethnicity, an association was detected in Caucasians (dominant model GG vs. GT + TT, OR = 0.833, 95% CI = 0.701—0.990, P = 0.038; recessive model GG + GT vs. TT, OR = 0.667, 95% CI = 0.456—0.975, P = 0.037; homozygote model GG vs. TT, OR = 0.636, 95% CI = 0.433—0.935, P = 0.021), and a possible association was detected in Asians in dominant model (GG vs. GT + TT, OR = 0.709, 95% CI = 0.503—0.998, P = 0.049). The details are shown in Table 4 and Fig. 4.
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Stat4 rs7574865 polymorphism and IBD Table 2
5
Allele and genotype information of IBD, CD, UC cases and controls.
Author
Type
Case
Control
G
T
GG
GT
TT
G
T
GG
GT
TT
Zhu H
CD UC IBD
220 51 271
236 61 297
19 4 23
182 43 225
27 9 36
269 269 269
273 273 273
39 39 39
191 191 191
41 41 41
Moon CM
CD UC IBD
254 325 579
110 167 277
89 97 186
76 131 207
17 18 35
312 312 312
146 146 146
106 106 106
100 100 100
23 23 23
Martínez A
CD UC IBD
494 541 1035
150 163 313
191 209 400
112 123 235
19 20 39
1160 1160 1160
272 272 272
470 470 470
220 220 220
26 26 26
Diaz-Gallo LM
CD UC IBD
807 619 1426
189 185 374
320 241 561
167 137 304
11 24 35
2054 2054 2054
538 538 538
813 813 813
428 428 428
55 55 55
Bouzid D
CD UC IBD
60 103 163
18 33 51
23 39 62
14 25 39
2 4 6
272 272 272
52 52 52
113 113 113
46 46 46
3 3 3
Pang Z
CD IBD
45 45
87 87
9 9
27 27
30 30
41 41
91 91
6 6
29 29
31 31
Glas J
CD UC IBD
1388 729 2117
326 199 525
NA NA NA
NA NA NA
NA NA NA
2171 2171 2171
595 595 595
NA NA NA
NA NA NA
NA NA NA
IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis.
Heterogeneity and publication bias No between-study heterogeneity was found in metaanalyses of the rs7574865 polymorphisms UC susceptibility in the overall population, in Caucasians, or in Asians. So fixed-effect models were used to calculate the relationship. However, obvious heterogeneity was detected in rs7574865
Table 3
polymorphism with IBD and CD susceptibility, after stratification by ethnicity, the heterogeneity still exists in some comparisons. So random-effect models were used to assess the relationship (Tables 3 and 4). The results of Egger’s linear regression test are shown in Tables 3 and 4. It was shown that there was no publication bias except for the comparisons of G vs. T in Caucasian population of rs7574865
Meta-analysis of the association between the STAT4 rs7574865 polymorphism and inflammatory bowel disease.
Comparison
G vs. T Allelic model
GG vs. GT + TT Dominant model GG + GT vs. TT Recessive model GG vs. TT Homozygote model
Ethnicity
Over all Caucasian Asian African Over all Caucasian Asian Over all Caucasian Asian Over all Caucasian Asian
No. of study
7 3 3 1 6 2 3 6 2 3 6 2 3
Test of association
Model
OR
95% CI
P-value
0.968 0.986 0.969 1.105 0.855 0.890 0.809 0.983 0.857 0.198 0.849 0.825 0.983
0.898—1.043 0.904—1.075 0.825—1.137 0.969—1.261 0.760—0.962 0.777—1.020 0.620—1.056 0.785—1.231 0.619—1.186 0.869—1.651 0.661—1.092 0.594—1.145 0.652—1.481
0.395 0.743 0.696 0.137 0.009 0.095 0.120 0.879 0.352 0.271 0.203 0.249 0.935
R R F NA R R F F R F F R F
Test of heterogeneity P-value
I2 (%)
0.023 0.008 0.754 NA 0.084 0.077 0.121 0.177 0.089 0.926 0.127 0.060 0.351
59.0 79.1 0.0 NA 48.6 67.9 52.6 34.5 65.5 0.0 41.8 71.8 4.5
Egger’s (P-value)
0.333 0.029 0.249 NA 0.507 NA 0.914 0.293 NA 0.349 0.605 NA 0.781
vs.: versus; F: fixed-effects model; NA: not available; OR: odds ratio; CI: confidence interval. Significant P-values (< 0.05) are in bold.
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CD
Comparison
G vs. T Allelic model
GG + GT vs. TT Recessive model GG vs. TT Homozygote model UC
G vs. T Allelic model
GG vs. GT + TT Dominant model GG + GT vs. TT Recessive model GG vs. TT Homozygote Model
No. of study
Test of association OR
95%CI
Model P-value
Test of heterogeneity
Egger’s (P-value)
2
P-value
I (%)
Over all Caucasian Asian African Over all Caucasian Asian Over all Caucasian Asian Over all Caucasian Asian
7 3 3 1 6 2 3 6 2 3 6 2 3
1.017 1.016 1.032 1.167 0.922 0.939 0.922 1.132 1.113 1.183 1.020 1.080 1.009
0.924—1.120 0.850—1.216 0.919—1.159 1.003—1.357 0.798—1.066 0.794—1.111 0.679—1.251 0.865—1.482 0.725—1.708 0.833—1.679 0.748—1.390 0.701—1.663 0.640—1.592
0.727 0.860 0.597 0.045 0.273 0.462 0.602 0.367 0.626 0.348 0.901 0.727 0.968
R F R NA R R R F R F R R F
0.076 0.706 0.013 NA 0.082 0.057 0.080 0.127 0.009 0.840 0.069 0.006 0.512
47.5 0.0 76.8 NA 48.9 72.5 60.5 41.8 85.4 0.0 51.1 86.9 0.0
0.457 0.422 0.291 NA 0.605 NA 0.995 0.471 NA 0.035 0.764 NA 0.596
Over all Caucasian Asian African Over all Caucasian Asian Over all Caucasian Asian Over all Caucasian Asian
6 3 2 1 5 2 2 5 2 2 5 2 2
0.881 0.898 0.891 1.004 0.788 0.833 0.709 0.798 0.667 1.198 0.683 0.636 0.941
0.798—0.972 0.802—1.005 0.711—1.117 0.838—1.203 0.679—0.914 0.701—0.990 0.503—0.998 0.593—1.074 0.456—0.975 0.725—1.980 0.498—0.937 0.433—0.934 0.524—1.688
0.012 0.061 0.317 0.966 0.002 0.038 0.049 0.137 0.037 0.482 0.018 0.021 0.838
F F F NA F F F F F F F F F
0.292 0.193 0.777 NA 0.501 0.397 0.384 0.239 0.781 0.420 0.345 0.687 0.207
18.7 39.2 0.0 NA 0.0 0.0 0.0 27.3 0.0 0.0 10.7 0.0 37.1
0.164 0.239 NA NA 0.032 NA NA 0.643 NA NA 0.362 NA NA
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GG vs. GT + TT Dominant model
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Meta-analysis of the association between the STAT4 rs7574865 polymorphism and Crohn’s disease and ulcerative colitis.
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vs.: versus; R: random-effects model; F: fixed-effects model; NA: not available; OR: odds ratio; CI: confidence interval. Significant P-values (< 0.05) are in bold.
Q.-F. Liu et al.
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
Table 4
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Stat4 rs7574865 polymorphism and IBD
Figure 2 disease.
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Forest plots for the meta-analysis of association between STAT4 rs7574865 polymorphism and inflammatory bowel
with IBD susceptibility, GG + GT vs. TT in Asian population of rs7574865 with CD susceptibility and GG vs. GT + TT in overall population of rs7574865 with UC susceptibility.
Sensitivity analysis To determine the stability of the results of this metaanalysis, one-way sensitivity analyses were performed by sequentially excluding individual studies. The pooled ORs of the rs7574865 polymorphism and IBD, CD or UC were not influenced by the results of any individual study, indicating the stability of the results (data not shown).
Discussion It is well recognized that there is individual susceptibility to IBD even with the same environmental exposure. Host factors, including polymorphisms of genes involved in IBD, may have accounted for this difference. Therefore, genetic factors are considered to be strong disease determinants, and this has encouraged researchers to search for the responsible genes. Recently, accumulating evidence indicates that STAT4 is a pathogenic factor in IBD, both in animal models [28,29] and in humans [30]. STAT4 expression is very low
in resting T cells and is upregulated by the stimulation of TCR in response to IL-12. Constitutive STAT4 activation was observed in the mucosa from UC patients and in intestinal T cells of CD patients [31]. Kaplan et al. [32] and Jacob et al. [33] studied in STAT4-knockout and transgenic mice have demonstrated the critical role of STAT4 in immune responses to inflammatory diseases. In addition, STAT4 is required for the signal transduction of various pro-inflammatory cytokines highlights an important role of STAT4 in the pathogenesis of autoimmune diseases, including IBD. In the past years, an increasing number of studies mainly conducted in Caucasians or Asians to assess the association of STAT4 gene polymorphism with IBD susceptibility, but these studies have not reached a consistent result. The main reason for this discrepancy may due to the small sample size have insufficient statistical power to detect a weak association in some negative studies. So it is pressed for a meta-analysis to summarize the individual study for producing a pooled result. The present meta-analysis examined the association of STAT4 rs7574865 gene to IBD susceptibility containing 3784 IBD patients and 4126 controls. Our results reveal a significant association of the SNP rs7574865 in the STAT4 gene with IBD susceptibility in overall population, which raises the possibility that STAT4 is a susceptibility genetic factor for
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Figure 3
Forest plots for the meta-analysis of association between STAT4 rs7574865 polymorphism and Crohn’s disease.
this complex disease. However, after we stratified by ethnicity, this association was disappeared in Asian population and Caucasian population, it is possible that stratification make sample size decreasing, so we have insufficient statistical power to detected a weak association. We further stratification by disease type, we detected a significant association of STAT4 rs7574865 gene polymorphism with UC susceptibility in overall population and Caucasian population, and a possible association was found in Asian population (P = 0.049). For this possible association, it’s may a false-positive result producing by various bias or a real positive result, we should interpret with cautious and further study with more sample size and adequate statistical power is needed to clarify this possible association. In addition, we failed to detect any association of STAT4 rs7574865 polymorphism with CD susceptibility in overall population, Caucasian population and Asian population, but a possible association was detected in African population (P = 0.045). This possible association was result from only one study, so we are not sure rs7574865 is a CD susceptibility risk factor in Africans, further studies with more sample size are needed for a definitive conclusion. Indeed, CD and UC share many characteristics, but some clinical features also distinguish them. CD and UC likely share some genetic susceptibility loci but differ at others [34]. In this respect, a number of genetic loci, such as the ATG16L1, IRGM, MIF, IL23R, and IL12B genes polymorphisms
associated with both diseases have been described. Meanwhile, the ECM1, ARPC2, and IL-10 genes as well as regions on chromosomes 1p36, 2q24-37, and 12q15 are mainly associated with UC. However, the NOD2 gene, which is strongly associated with CD, is not a risk factor for UC susceptibility [2,34]. These differences may be caused by pleiotropic effects of specific genes on a common polygenic and multifactor background. The distinct influence of the STAT4 gene on IBD risk observed in our study provides an example of the differences in genetic background between these two intestinal inflammatory disorders [20]. The etiology of IBD, of which UC and BD are the two most prevailing entities, is unknown. However, IBD is characterized by an imbalanced synthesis of pro-inflammatory mediators of the inflamed intestine, and for more than a decade tumor necrosis factor-␣ (TNF-␣) has been a major target for monoclonal antibody therapy. However, TNF inhibitors are not useful for one third of all patients (i.e. ‘‘primary failures’’), and further one third lose effect over time (‘‘secondary failures’’). Therefore, other strategies have in later years been developed. Recently, STAT4 have been reported play a important roles in the pathogenesis of IBD. STAT4 represents a transcription factor transducing IL-12-, IL-23-, and type 1 interferon-mediated signals into Th1 and Th17 differentiation, monocyte activation, and interferon-gamma production. In our study, we clarify the
Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002
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Stat4 rs7574865 polymorphism and IBD
Figure 4
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Forest plots for the meta-analysis of association between STAT4 rs7574865 polymorphism and ulcerative colitis.
association between STAT4 rs7574865 polymorphism and IBD susceptibility, and found this SNP is associated with IBD and UC. Thus, STAT4 can be the diagnostic and therapeutic potential for IBD and UC. Drug development for IBD holds great promise, and patients as well as their treating physicians can be hopeful for the future. Similar as most other gene-related meta-analysis, some limitations of this study should be discussed. First, the number of studies included in the meta-analysis may be insufficient to detect slight associations, and the number of studies in some comparisons are relatively small, which may mean that our investigation was underpowered. Second, publication biases were detected in some comparisons, which may distort the results of this meta-analysis. Third, significant between-study heterogeneity was detected in IBD and CD studies. But it was not a major problem, because IBD and CD itself are heterogeneous. In conclusion, this meta-analysis provides evidence of the association between the STAT4 rs7574865 polymorphism and the risk of IBD, hinting that STAT4 rs7574865 polymorphism may play a role in IBD susceptibility. This meta-analysis also reveals STAT4 rs7574865 polymorphism is associated with UC susceptibility, especially in Caucasian population, but not associated with CD susceptibility in overall, Caucasian and Asian population, respectively. To confirm our findings, further studies with subtle study design based on larger sample size, case-control design, and stratification by ethnicity are still needed.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Please cite this article in press as: Liu Q-F, et al. Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.04.002