Oncotarget

Meta-Analysis:

Comprehensive assessment of the association between estrogen receptor of alpha polymorphisms and the risk of prostate cancer: evidence from a meta-analysis

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Oncotarget. 2017; 8:102310-102320. https://doi.org/10.18632/oncotarget.21117

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Guang Li, Meng Yang, Xian Li _ and Shixiong Deng

Abstract

Guang Li1,*, Meng Yang2,*, Xian Li3 and Shixiong Deng1

1Laboratory of Forensic Medicine and Bioinformatics, Chongqing Medical University, Chongqing, China

2Research Department, Children Hospital of Chongqing Medical University, Chongqing, China

3Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China

*These authors contributed equally to this work

Correspondence to:

Xian Li, email: lixian810@gmail.com

Shixiong Deng, email: dengshixiong1963@163.com

Keywords: estrogen receptor of alpha, polymorphisms, prostate cancer, meta-analysis

Received: June 22, 2017     Accepted: August 27, 2017     Published: September 21, 2017

ABSTRACT

We performed a meta analysis to access the relationship of estrogen receptor of alpha (ESRα) polymorphisms with the risk of prostate cancer (PC). Twenty-four case-control studies (including 5477 cases and 10708 controls) were recruited for meta-analysis. The strongest association with the risk of PC was observed between ESRα rs9340799 and rs2234693 under the two genotypic models of allele and codominance in the overall population (p < 0.05). Under the subgroup analysis of ethnicity, we observed that ESRα rs9340799 was significantly associated with the susceptibility to PC in European population (AvsG, p = 0.000; AAvsGG, p = 0.002), while there was no difference in Asian (AvsG, p = 0.493; AAvsGG, p = 0.736) or African population (AvsG, p = 0.800; AAvsGG, p = 0.788). The results also showed that significant association between rs2234693 and the susceptibility to PC in European (CvsT, p = 0.004; CCvsTT, p = 0.001) and Asian population (CvsT, p = 0.004; CCvsTT, p = 0.003), but not in African population (CvsT, p = 0.636; CCvsTT, p = 0.669). The meta-analysis indicated that ESRα rs9340799 and rs2234693 might contribute to susceptibility and development of PC in European population.


INTRODUCTION

Prostate cancer (PC) is a common malignant tumor occurring in males and has become the predominant cause of death among males, which accounts for about 10% of male mortality [1]. However, the pathogenesis of PC remains to be determined. Several studies reported that both genetic susceptibility and environmental factors such as diet and lifestyle exerted major influences on the occurrence of PC [2]. In particular, single nucleotide polymorphism (SNP) derived from single nucleotide point mutation was considered to be one of the important material carriers with genetic susceptibility [3]. As the third generation genetic marker, SNP was polymorphic and derived from the variation of individual nucleotide at the same site of DNA sequence. Due to the diversity in diet, geological areas and genetic factors, the incidences of PC among races remained differences and similarities. Estrogen receptor of alpha (ESRα), found by Jensen in 1971, was an estrogen-dependent transcription factor, and located at the Zone 1, Area 25 of long-arm of the No. 6 chromosome (6q25.1), and the polymorphic sites of its intron and exon areas had been already identified [4]. Meanwhile, as a member of nucleus receptor super-family, ESRα could transfer into nucleus of PC cells in combination with estrogen, regulate the signal pathways of gene transcription and promote cell proliferation [5]. Currently, A number of anti-cancer drugs play important roles in disturbing and hindering the combination of the nodes to achieve the therapeutic goal [6]. It is possible that the development of PC may be affected by the SNP site of ESRα. However, the results were not always consistent [912]. Different regional and ethnic groups varied from inherit susceptibility genes and SNPs due to the highly genetic heterogeneity of PC.

Although there are several studies on investigating the interactions between ESRα and PC among Asians, Europeans and Africans [7, 8], the inconsistency of findings exists. Remarkably, both sites of rs9340799 and rs2234693 have been widely studied in ESRα genetic polymorphisms [912], but ESRα rs9340799 or rs2234693 were independent of PC susceptibility because of quality and quantity limitations. The meta-analysis of ESRα rs9340799 and rs2234693 was firstly conducted by Ding [10] in 2012, indicating that rs9340799, not rs2234693, confered an elevated risk of PC. Gu’s study [11] demonstrated that there was no significant difference between 4,884 case groups and 10,134 control groups in rs2234693 regardless of allele or other models (allele model, OR = 0.98; 95 % CI, 0.88–1.08; P = 0.685; dominant model, OR = 0.98; 95 % CI, 0.89–1.07; P = 0.685; recessive model, OR = 0.96; 95 % CI, 0.81–1.14; P = 0.657; homozygous model, OR = 0.96; 95 % CI, 0.77–1.19; P = 0.708; heterozygous model, OR = 0.96; 95 % CI, 0.81–1.13; P = 0.708, respectively). On the other hand, G in rs9340799 may be related to PC susceptibility (allele model, OR= 1.09; 95 % CI, 1.03–1.17; P = 0.006; dominant model, OR = 1.17; 95 % CI, 1.07–1.29; P = 0.001; homozygous model, OR = 1.17; 95 % CI, 1.01–1.35; P = 0.040; respectively), especially in Africans (allele model, OR = 1.53; 95 % CI, 1.13–2.07; P = 0.006; dominant model, OR = 1.78; 95 % CI, 1.19–2.66; P = 0.005; homozygous model, OR = 2.04; 95 % CI, 1.00–4.14; P = 0.049, respectively). In contrast, such connections had not been indentified yet in Europeans or Asians, as reported in Ding’s publications. Fu’s research[9] presented that rs9340799 polymorphism was significantly associated with PC in overall populations (GG+GA vs. AA: P= 0.002; G vs. A: P = 0.004), Caucasians (GG+GA vs. AA: P = 0.008; G vs. A: P = 0.016) and Africans (GG+GA vs. AA: P= 0.005; G vs. A: P = 0.006), but not in Asians (GG+GA vs. AA: P = 0.462; G vs. A: P = 0.665). Another study [12] regarding 4,623 cases of PC patients pointed out that rs2234693 in overall populations was markedly involved in PC susceptibility (P < 0.05), and the polymorphism CC may increase the risks of PC. Moreover, ethnic subgroup analysis revealed that the site had a close correlation with Europeans (P < 0.05), but not with Asians or Africans (P > 0.05).

It has been shown that there is certain correlation between PC susceptibility and ESRα rs9340799 or rs2234693, but unanimous conclusion has not been reached yet in the repetitive studies. Therefore, it remains to be verified further. This study aims to assess the association of ESRα sites rs9340799, rs2234693 and the susceptibility of PC according to all published literatures using Cochrane system assessment method. These findings will provide reliable evidence for therapeutic approahes in PC disease.

RESULTS

Studies included in the meta-analysis

In the meta-analysis, totally 112 relevant articles were obtained under some fundamental restrictions. After filtering, 24 eligible articles [1437] were finally selected on the basis of the inclusion and exclusion criteria. The flow chart of selecting articles process was presented in Figure 1. Therefore, there were 41 independent case-control studies in total, and the genotype distribution of control group was based on Handy-Weinberg. For ESRα rs9340799, there were 17 studies involving a total of 3960 PC cases and 4848 normal controls. For ESRα rs2234693, 24 studies (5477 PC cases and 10708 normal controls) were available, respectively. The main characteristics of these included studies were shown in Table 1.

The flow chart of article selected in meta-analysis.

Figure 1: The flow chart of article selected in meta-analysis.

Table 1: The main characteristics of all eligible studies in meta-analysis

Study

Sample size (case/control)

Genotype Distribution (case)

Genotype Distribution (control)

Ethnicity

HWE p-value

ESRα rs9340799 (A>G)

AA

AG

GG

AA

AG

GG

1

Modugno

2001

82

237

34

38

10

116

93

28

Caucasian

0.175

2

Suzuki

2003

101

114

72

24

5

75

30

9

Asian

0.147

3

Fukatsu

2004

117

242

74

37

6

163

68

11

Asian

0.286

4

Hernandez(a)

2006

120

303

56

51

13

153

119

31

Caucasian

0.274

5

Hernandez(b)

2006

431

582

182

191

58

229

281

72

Caucasian

0.371

6

Hernandez(c)

2006

47

213

17

25

5

117

77

19

African

0.226

7

Cunningham

2007

918

487

370

417

121

189

227

71

Caucasian

0.847

8

Beuten(a)

2009

82

209

37

36

9

118

78

13

African

1

9

Beuten(b)

2009

195

371

91

84

20

224

88

59

Caucasian

1

10

Beuten(c)

2009

609

843

258

277

74

335

393

115

Caucasian

1

11

Gupta

2010

157

170

71

75

11

87

72

11

Asian

0.565

12

Sissung

2010

129

127

42

69

18

58

61

8

Caucasian

0.146

13

Balistreri

2011

50

47

34

13

3

42

4

1

Caucasian

0.156

14

Szendroi

2011

205

101

35

111

59

29

54

18

Caucasian

0.545

15

Safarinejad

2012

162

324

20

108

34

81

187

56

Caucasian

0.05

16

Jurecekova

2013

311

256

110

145

56

119

105

32

Caucasian

0.259

17

Han

2017

244

222

148

84

12

142

70

10

Asian

0.68

ESRα rs2234693 (C>T)

CC

CT

TT

CC

CT

TT

1

Modugno

2001

81

237

21

34

26

43

109

85

Caucasian

0.424

2

Tanaka

2003

115

200

29

63

23

48

113

39

Asian

0.088

3

Suzuki

2003

101

114

12

43

46

26

59

29

Asian

0.851

4

Fukatsu

2004

116

238

22

57

37

47

110

81

Asian

0.427

5

Hernandez(a)

2006

120

303

18

55

47

43

131

129

Caucasian

0.318

6

Hernandez(b)

2006

431

582

100

216

115

132

296

154

Caucasian

0.679

7

Hernandez(c)

2006

47

213

16

22

9

50

113

50

African

0.413

8

Low

2006

75

158

21

41

13

25

84

49

Caucasian

0.329

9

Cunningham

2007

924

489

213

454

257

120

249

120

Caucasian

0.718

10

Berndt

2007

470

603

111

238

121

135

316

152

Caucasian

0.254

11

Kjaergaard

2007

116

4005

26

55

35

830

1972

1203

Caucasian

0.676

12

Sobti

2008

157

170

52

77

28

64

90

16

Asian

1

13

Onsory

2008

100

100

18

54

28

10

48

42

Asian

0.656

14

Beuten(a)

2009

82

209

23

41

18

50

105

54

African

1

15

Beuten(b)

2009

195

514

28

92

75

82

246

186

Caucasian

1

16

Beuten(c)

2009

609

843

138

304

167

200

421

222

Caucasian

1

17

Gupta

2010

157

170

28

77

52

16

90

64

Asian

0.066

18

Sonoda

2010

180

177

31

89

60

29

87

61

Asian

0.878

19

Sissung

2010

128

126

28

75

25

20

60

46

Caucasian

1

20

Szendroi

2011

204

103

39

122

43

25

47

31

Caucasian

0.43

21

Safarinejad

2012

162

324

57

94

11

90

169

65

Caucasian

0.434

22

Jurecekova

2013

311

256

79

154

78

49

126

81

Caucasian

1

23

Lu

2015

352

352

94

191

67

97

175

80

Asian

0.95

24

Han

2017

244

222

48

102

94

34

96

92

Asian

0.313

Meta-analysis results

ESRα rs9340799 polymorphism and susceptibility to PC. To assess the association of ESRα rs9340799 polymorphism with PC, 17 studies were included in this meta-analysis with 3960 PC cases and 4848 normal controls (Table 2). Both allele and additive models were tested in the overall population. PC susceptibility in Caucasian population showed strong association in the allele model (AvsG), and patients carrying mutant gene A were 0.84 times incidence rate of susceptibility to PC (OR = 0.84, 95 CI%: 0.72–0.96, P = 0.000). In the additive model (AAvsGG), PC case group obtained 0.75 times of probability on AA genotype and enhanced the risk of disease (OR = 0.75,95% CI, 0.56–1.00, P = 0.002). In contrast, there was no significant association between Asian and African populations in all the models. Detailed results were listed in Table 2. Test of heterogeneity in the other models (AAvsAG+GG, AA+AGvsGG, AGvsGG) were not significant among different races of populations.

Table 2: Meta-analysis of the association between ESRα rs9340799 and prostate cancer

ESRα rs9340799

AvsG (allele model)

AAvsGG (additive model)

Population

N

OR (95% CI)

Ph

POR

OR (95% CI)

Ph

POR

Overall

17

0.84 (0.75–0.94)

0.002

0.001

0.77 (0.61–0.97)

0.038

0.011

Caucasian

11

0.84 (0.72–0.96)

0.015

0.000

0.75 (0.56–1)

0.076

0.002

Asian

4

0.92 (0.77–1.11)

0.410

0.493

0.96 (0.59–1.55)

0.874

0.736

African

2

0.65 (0.48–0.88)

0.015

0.800

0.49 (0.24–1)

0.049

0.788

ESRα rs2234693

CvsT (allele model)

CCvsTT (additive model)

Population

N

OR (95%CI)

Ph

POR

OR(95%CI)

Ph

POR

Overall

24

1.09 (1.00–1.18)

0.037

0.000

1.21 (1.01–1.44)

0.030

0.000

Caucasian

13

1.11 (1.00–1.23)

0.070

0.004

1.26 (1.01–1.58)

0.062

0.001

Asian

9

1.02 (0.86–1.21)

0.571

0.004

1.05 (0.72–1.52)

0.517

0.003

African

2

1.24 (0.94–1.64)

0.134

0.636

1.52 (0.86–2.69)

0.143

0.669

OR odd ratio, 95% CI confidence interval, POR value for the test of association, Ph value for heterogeneity analysis.

ESRα rs2234693 polymorphism and susceptibility to PC. There were 24 studies with 5477 PC cases and 10708 normal controls in this meta-analysis to evaluate the association of ESRα rs2234693 polymorphism with PC (Table 2). In allele model, the risk genotype of wild type T was used to assess the relationship between C gene mutation and susceptibility to PC. Our results showed that there was statistical heterogeneity among these studies (I2 = 56.75, P = 0.003), so the random effects model was chosen for meta-analysis. As shown in Figure 2 and Figure 3, forest maps presented that PC patients carrying C genotype got a higher risk than people with T genotype (OR = 1.09, 95% CI:1.00–1.18, P = 0.000), especially in the European (OR = 1.11, 95% CI:1.00–1.23, P = 0.004) and Asian populations (OR = 1.02, 95% CI:0.86–1.21, P = 0.004), however, Africans were not correlated with either genotype (OR = 1.24, 95% CI:0.94–1.64, P = 0.636). In the dominant model, with TT genotype reference, mutation homozygous CC genotype was evaluated and discussed with PC susceptibility. Meta-analysis was conducted with a random effects model (I2 = 59.8, P = 0.001), CC genotype in overall population was more inclined to PC than people with TT genotype (OR = 1.21, 95% CI:1.01–1.44, P = 0.000). The result in different races was consistent with allele model that there was the remarkable relationship in European or Asian populations, but no correlation in African populations (Europeans, OR = 1.26, 95% CI:1.01–1.58, P = 0.001; Asians, OR = 1.05, 95% CI:0.72–1.52, P = 0.003; Africans, OR = 1.52, 95% CI:0.86–2.69, P = 0.669). Other models (CCvsCT+TT, CC+CTvsTT, CTvsTT) were not heterogeneous among different races, either.

Forest plot of the association between ESR1 rs9340799 and prostate cancer risk(AvsG, AAvsGG).

Figure 2: Forest plot of the association between ESR1 rs9340799 and prostate cancer risk(AvsG, AAvsGG).

Forest plot of the association between ESR1 rs2234693 and prostate cancer risk(CvsT, CCvsTT).

Figure 3: Forest plot of the association between ESR1 rs2234693 and prostate cancer risk(CvsT, CCvsTT).

Allele frequency of ESRα rs9340799, rs2234693 and comparing to the 1000 genome population

In Table 3, we demonstrated the distinct difference of allele frequencies in Caucasian, Asian and African populations in the meta-analysis of ESRα rs9340799 and rs2234693, which were consistent with the data of 1000 genome population project, European ancestry (EUR), Asian ancestry (EAS), African ancestry (AFR).

Table 3: The allele frequency comparison between the meta-analysis and 1000 genomes project

ESRα rs9340799

Meta-analysis (alleles frequencies)

1000 Genomes (alleles frequencies)

Populations

Cases

Controls

A

G

A

G

A

G

Caucasian

0.620

0.380

0.647

0.353

0.308 EUR

0.692 EUR

Asian

0.767

0.233

0.785

0.215

0.194 EAS

0.806 EAS

African

0.655

0.345

0.741

0.259

0.265 AFR

0.735 AFR

All

0.644

0.356

0.677

0.323

0.281 ALL

0.719 ALL

ESRα rs2234693

Meta-analysis (alleles frequencies)

1000 Genomes (alleles frequencies)

Populations

Cases

Controls

C

T

C

T

C

T

Caucasian

0.482

0.518

0.457

0.543

0.423 EUR

0.577 EUR

Asian

0.467

0.533

0.462

0.538

0.400 EAS

0.600 EAS

African

0.547

0.453

0.495

0.505

0.570 AFR

0.430 AFR

All

0.467

0.533

0.460

0.540

0.446 ALL

0.554 ALL

EUR European ancestry, EAS Asian ancestry, AFR African ancestry, ALL All individuals from phase 1 of the 1000 Genomes Project.

Publication bias and sensitivity analysis

Begg’s funnel plot and Egger’s test were performed to estimate publication bias. As shown in Figures 4 and Figure 5, the funnel plots presented scattered distribution but large symmetry, indicating that there was no obvious evidence of publication bias in ESRα rs9340799 (AvsG P = 0.081, AAvsGG, P = 0.111) and ESRα rs2234693 (CvsT, P = 0.166, CCvsTT, P = 0.136). In addition, we conducted sensitivity analysis to assess the stability of meta-analysis between ESRα rs2234693 and PC risk. As shown in Figure 6 and Figure 7, there was no significant difference, suggesting that articles selected in this research were available.

Begg&#x2019;s funnel plot of publication bias in meta-analysis of the association between ESR1 rs9340799 and prostate cancer risk(AvsG, AAvsGG).

Figure 4: Begg’s funnel plot of publication bias in meta-analysis of the association between ESR1 rs9340799 and prostate cancer risk(AvsG, AAvsGG).

Begg&#x2019;s funnel plot of publication bias in meta-analysis of the association between ESR1 rs2234693 and prostate cancer risk(CvsT, CCvsTT).

Figure 5: Begg’s funnel plot of publication bias in meta-analysis of the association between ESR1 rs2234693 and prostate cancer risk(CvsT, CCvsTT).

Sensitive analysis to assess the stability of meta-analysis between ESR1 rs9340799 and prostate cancer risk(AvsG, AAvsGG).

Figure 6: Sensitive analysis to assess the stability of meta-analysis between ESR1 rs9340799 and prostate cancer risk(AvsG, AAvsGG).

Sensitive analysis to assess the stability of meta-analysis between ESR1 rs2234693 and prostate cancer risk(CvsT, CCvsTT).

Figure 7: Sensitive analysis to assess the stability of meta-analysis between ESR1 rs2234693 and prostate cancer risk(CvsT, CCvsTT).

DISCUSSION

ESRα is a kind of ligand-activated nuclear transcription factor and mainly distributes at the clearance between the basal epithelial cells and the matrix of the prostate. The gene coded ESRα was located at 6q25.1 of the human chromosome, which possessed 140,000 bp and consisted of eight exons and seven introns. Two of the most common polymorphic sites in ESRα were rs9340799 and rs2234693, both of which were situated in the first intron with 50 bp of distance, the same as the positive chromosome area using large-scale genetic scanning chain analysis as reported previously [37]. The first intron lied at the end of amidogen, which was located in the main transcriptional domain, and contained the major adjustment sequences such as promoters and enhancers. Base T/C or A/G substitution in the area may cause the loss of existed restriction enzyme site and produce a new one instead, and each behavior may lead to the error splicing and bring abnormal expression products. In addition, estrogen wouldn’t work without combining with ESRα, and the abnormal ESRα expression would directly induce the ultimate physiological effect of the estrogen in body, and finally affect the occurrence and development of PC. Therefore, it is likely that the genetic polymorphisms at ESRα rs9340799 and rs2234693 may contribute to the risk of PC.

So far there were four published papers [912] in this meta-analysis concerning the association of the polymorphisms of ESRα (rs9340799 or rs2234693) with PC susceptibility. However, the number of references regarding those results was unstable due to different publication period and standard for data screening. In this paper, 17 studies on ESRα rs9340799 and 24 studies on ESRα rs2234693 were included according to the strict inclusion and exclusion critiria, through searching in both Chinese and English databases. We found that there was statistically significant difference in distribution frequency of genetic polymorphisms of ESRα allelic genes between cases and controls (p < 0.05). Further analysis on PC patients from different races indicated that both base A and AA of ESRα rs9340799 may increase the risk of PC in overall population, particularly in European, however, the association was not significant in the populations of Asian and African. Similarly, a remarkable correlation was found in base C and CC of ESRα rs2234693 in Europeans and Asians, suggesting a higher risk of PC in these populations than that in Africans. Considering the limited samples from only two studies in African in this meta-analysis, studies with larger sample size including diverse ethnic populations are required to investigate the association between the polymorphisms of ESRα and the susceptibility of PC.

Consistent with the report of Gu [11], we observed that there was a certain correlation between PC and ESRα rs9340799, and the precision of such correlation reached to polymorphism of the site, which induced an affirmative result through further study on larger samples. Meanwhile, it should be noted that the control group of ESRα rs9340799 had no representativeness in the h-w genetic balance test according to the standard of P > 0.05, while it was still acceptable if the standard was P > 0.01. All results in this study were selected according to the standard of P > 0.05, therefore, larger sample size was required in the future. Besides, different conclusions were reached in this study on the correlation between the genetic sites of ESRα rs2234693 and PC compared with previous studies. On the one hand, as reported before, PC was a kind of disease affected by multiple genes, which induced various clinical features. It was inevitable to reach negative results if the samples were inadequate or assigned randomly.

It is worth mentioning that there were still have several limitations in this meta-analysis: 1) For lack of linguistic experience, databases used in this study were limited to English and Chinese; 2) This study focused on the analysis on ESRα rs9340799 and rs2234693 only, without considering the interactions between other genes and environmental factors. Therefore, stricter design was needed to control destructive factors, and larger samples and homogeneous cases were required in the comparable and prospective studies. At the same time, the interactions between the genes and environmental factors would be fully considered in the pathogenesis of PC, which provided more reliable evidences for basic study and clinical treatment.

Despite the limitations, this meta-analysis revealed that ESRα rs9340799 and rs2234693 were associated with susceptibility to PC, and studies with larger sample size are needed to define the association between the polymorphisms of ESRα rs9340799 and rs2234693 and the risk of PC in the future.

MATERIALS AND METHODS

The inclusion and exclusion criteria

Inclusion criteria: (1) the type of study was case-control; (2) cases were histologically diagnosed with PC patients, the pathological type was adenocarcinoma, control group was unrelated healthy people; (3) the distribution of genotypes was fully justified with Hardy-Weinberg genetic balance law; (4) the literature provided a complete genotype data. Exclusion criteria: (1) there was only case but without control group; (2) study which was repetitive publication; (3) incomplete data [13].

Literature search

Keywords “single nucleotide polymorphism or SNP or variants”, “prostate cancer or carcinoma”, “estrogen receptor alpha or ESR1”, were searched in PubMed, Embase, Cochrane Library, China Biology Medicine (CBM), China science and technology journal database (VIP), Chinese national knowledge infrastructure (CNKI) and Wanfang data knowledge service platform, from its inception to May 2017.

Quality assessment and data selection

Two researchers independently read abstracts, and the eligible literatures were intensively read for further study. Any differences were settled by discussion or the third researcher who decided whether be taken into the following. Quality of included reference were evaluated with Cochrane Reviewer ‹s Handbook 5 System Evaluation Handbook: (1) the diagnostic criteria was clear; (2) the sample size was sufficient; (3) the case and control groups were comparable; (4) statistical analysis method was appropriate; (5) existence of bias was discussed. Each term above was recorded 1 points, > 2 points for reliable quality. The following data was extracted from each included literature: the first author, year of publication, sample size, race, genotype frequency of case and control group, Handy-Weinberg.

Statistical processing

Meta-analysis was performed with Stata software. Q-test and I2-test were firstly used to judge the heterogeneity. Q-test P > 0.1 or I2 < 50% indicated that no significant heterogeneity was found between these studies, instead, fixed effect model should be used to combine. On the contrary, Q-test P < 0.1 or I2 > 50% stood for heterogeneity between these results, and such heterogeneity was not found from clinic, therefore, these data was merged using a random effect model. The combined odds ratio (OR) and 95% confidence intervals (CI) were then calculated, and difference (P < 0.05) was regarded as statistical significance. Egger’s and Begg ‘s test was applied to assess the publication bias. At last, OR value distribution was demonstrated with forest map, funnel plots and sensitive graphs, respectively.

CONFLICTS OF INTEREST

The authors declared that they have no conflicts of interest to this work.

FUNDING

This work was supported by the Chongqing Scientific Research Innovation Project (CYB16094; to G.L).

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