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The associations between the polymorphisms in the CTLA-4gene and the risk of Graves’ disease in the Chinese population

  • Liang Du1, 2Email author,
  • Jiqiao Yang1,
  • Jichong Huang1,
  • Yaxian Ma1,
  • Haichuan Wang1,
  • Tianyuan Xiong1,
  • Zhangpeng Xiang1,
  • Yonggang Zhang1 and
  • Jin Huang1Email author
BMC Medical Genetics201314:46

DOI: 10.1186/1471-2350-14-46

Received: 17 October 2012

Accepted: 8 April 2013

Published: 19 April 2013

Abstract

Background

The associations between the polymorphisms in Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) gene and Graves’ disease (GD) have been extensively investigated in Chinese population. However, the results were inconsistent. The objective of this study is to investigate the associations between the polymorphisms in CTLA-4 gene and the risk of GD by meta-analysis.

Methods

We searched Pubmed database, Medline (Ovid) database, CNKI database and Wanfang database, covering all studies until August 11, 2012. Statistical analysis was performed by using the Revman4.2 software and the Stata10.0 software.

Results

A total of 28 case–control studies concerning the most widely studied three polymorphisms [+49A/G(rs231775), -318C/T(rs5742909) and CT60(rs3087243)] for Chinese population in 21 publications were included. The results suggested that the G allele carriers (GG+GA) might have an increased risk of GD when compared with the AA homozygote carriers for the +49A/G polymorphism (GG+GA vs. AA: OR = 2.57, 95%CI = 1.87-3.52). However, as to the -318C/T polymorphism and CT60 polymorphism, the results indicated that the variant allele carriers might have decreased risks of GD when compared with the homozygote carriers (−318C/T: TT+TC vs. CC: OR = 0.78, 95%CI = 0.62-0.97; CT60: AA+AG vs. GG: OR = 0.64, 95%CI = 0.52-0.78).

Conclusions

The current meta-analysis indicated that the polymorphisms in the CLTA-4 gene might be risk factors for GD in the Chinese population. In future, more large-scale case–control studies are needed to validate these results.

Keywords

Graves’ disease CTLA-4 Polymorphism Chinese Meta-analysis

Background

Graves’ disease (GD) is a complex autoimmune thyroid disease, which is caused by excessive production of thyroid hormone and characterized by an enlarged thyroid gland, protrusion of the eyeballs, a rapid heartbeat and nervous excitability [1]. It is reported that GD occurs in about 1.2% in Western population and 0.25–1.09% in Chinese population [2]. It is widely accepted that GD is caused by complex interactions between many genetic factors and environmental factors. Numerous studies have been published focusing on the topic of genetic factors of GD risk in the Chinese population. Many genes involved in the inception and evolution of GD have been identified as GD candidate genes, such as ADRB2 [3], TSHR [4], CTLA-4 [5] and IL-13 gene [6]. And among them, the CTLA-4 gene is one of the most extensively studied.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a T cell surface molecule [7]. It is a negative regulator of T cell activation and plays an important role in the pathogenesis of GD. The CTLA-4 gene is localized on chromosome 2q33. Many polymorphisms have been identified in the CTLA-4 gene. It is reported that the polymorphisms in CTLA-4 gene might influence the expression of the protein, and might play important roles in the pathogenesis of GD [8]. Up to now, many studies have been performed to investigate the associations between the polymorphisms in the CTLA-4 gene and the risk of GD. Among them, the +49A/G, -318C/T and CT60 polymorphisms were the most widely studied. To this day, the associations between polymorphisms of the CTLA-4 gene and the risk of GD have been widely investigated in the Chinese population. However, the results were inconsistent, and the associations were not yet formally evaluated. In order to derive a more precise conclusion, we performed a meta-analysis to assess the associations between the polymorphisms in the CTLA-4 gene and the risk of GD in the Chinese population. To our knowledge, this is the first comprehensive genetic meta-analysis performed in the Chinese population for Graves’ disease.

Methods

Study identification and selection

A literature search in Pubmed database, Medline (Ovid) database, CNKI database and Wanfang database was carried out to identify studies investigating the association between the Graves’ disease risk and the CTLA-4 polymorphisms on Aug 11th, 2012. The search terms were as follows: Graves’ disease or GD in combination with polymorphism or variant or mutation and in combination with CTLA-4 or Cytotoxic T lymphocyte-associated molecule-4. All languages were included. The inclusion criteria were: (a) studies evaluating the association between the (+49A/G, -318C/T and CT60) polymorphisms in the CTLA-4 gene and Graves’ disease risk in the Chinese population, (b) the design should be a case–control design, (c) sufficient data (genotype distributions of cases and controls) available to calculate an odds ratio (OR) with its 95%CI (confidence interval), (d) genotype distributions in control group should be consistent with Hardy-Weinberg equilibrium (HWE). Studies were excluded if one of the following existed: (a) the studied populations were based on family or sibling pairs, (b) genotype frequencies or numbers were not presented in the original studies, (c) reviews and abstracts. If more than one study was published by the same authors using the same case series or overlapping case series, studies with the largest size of samples were included.

Data extraction

Two investigators independently extracted the data and reached a consensus on all items. The following items were extracted from each study if available: first author’s name, publication year, province of origin, age of cases, genotype number in cases and controls and genotyping method.

Statistical analysis

The strength of associations between the polymorphisms in the CTLA-4 gene and Graves’ disease risk was assessed by odds ratios (OR) with the corresponding 95% confidence intervals (CI). The genetic models evaluated for the pooled OR of the polymorphisms were dominant models (GG+GA vs. AA for the +49A/G, TT+TC vs. CC for the -318C/T, and AA+AG vs. GG for the CT60). OR was analyzed by a fixed-effects model (the Mantel-Haenszel method) or a random-effects model (the DerSimonian and Laird method) according to the heterogeneity. Heterogeneity was assessed by a X 2 based Q statistic and was considered statistically significant at p-value <0.10. When the P value was more than 0.10, the pooled OR was calculated by the fixed-effects model, otherwise, a random-effects model was used. The significance of the pooled OR was determined by the Z-test and p-value less than 0.05 was considered as statistically significant. Sensitivity analysis was conducted by sequential excluding a single study each time in an attempt to identify the potential influence of the individual data set to the pooled ORs. In addition, the possible publication bias was investigated with the Begg’s funnel plot. Funnel plot asymmetry was assessed by Egger’s linear regression test [9]. For each polymorphism, other genetic models were also used to assess the association with the risk of Graves’ disease (for the +49A/G polymorphism: GG vs. AA+GA, GG vs. AA, GA vs. AA, G vs. A; for the -318C/T polymorphism: TT vs. CC+TC, TT vs. CC, TC vs. CC, T vs. C; for the CT60 polymorphism: AA vs. AG+GG, AA vs. GG, AG vs. GG, A vs. G). HWE was tested by Person’s X 2 test. Statistical analysis was performed using Revman4.2 software and Stata10.0 software.

Results

Studies selection and characteristics

The selection process of studies was as follows. Briefly, a total of 429 results were identified after an initial search from the Pubmed, Medline (Ovid), CNKI and Wanfang databases. After reading the titles and abstracts, 302 results were excluded for being irrelevant to CTLA-4 polymorphisms and Graves’ disease risk, abstracts, reviews or duplications of search results. After reading full-texts of the remaining 127 studies, 68 studies were excluded for not relevant to the GD risk in the Chinese population, and 9 studies were excluded for not relevant to the investigated polymorphisms (+49A/G, -318C/T and CT60). Thus, 50 studies were left for data extraction. And then, a total of 54 case–control studies were extracted for these three polymorphisms. Among 54 case–control studies, genotype numbers for control group in 7 studies were not consistent with HWE, data in 19 studies were overlapped. So these 27 case–control studies were excluded. Finally, a total of 28 case–control studies in 21 publications were identified for meta-analysis [2, 1027]. Summary of the properties of the studies are listed in Table 1. Overall, there were 17 case-controls studies for the +49A/G polymorphism [2, 5, 1113, 15, 1725, 27, 28], 7 case–control studies for the -318C/T polymorphism [2, 1012, 14, 26, 28] and 4 case–control studies for the CT60 polymorphism [2, 10, 16, 18]. The genotype distributions for these polymorphisms are listed in Table 2.
Table 1

Properties of the 21 case–control studies included in meta-analysis

Author

Publication year

Province

Case age(year)

Case number

Control number

Genotyping method

Polymorphisms

Chong, K K [10]

2008

Hong Kong

<16

177

151

PCR-RFLP

−318C/T, CT60

Du, Y T [11]

2005

Tianjin

-

96

60

PCR-PFLP

+49A/G, -318C/T

Guo, Z Q [12]

2010

Shandong

44.17 ± 1.54

102

100

PCR-PFLP

+49A/G, -318C/T

Han, S Z [2]

2006

Chongqing

-

263

196

PCR-PFLP

+49A/G, -318C/T, CT60

Jiang, B R [13]

2005

Shandong

43.8 ± 13.5

98

95

PCR-PFLP

+49A/G

Kang, Y Z [14]

2010

Ningxia

43.7 ± 11.5

61

60

PCR-PFLP

−318C/T

Shen, F X [15]

2005

Zhejiang

36.0 ± 12.3

107

57

PCR-PFLP

+49A/G

Tsai, S T [16]

2008

Taiwan

10.2 ± 3.3

189

620

PCR-RFLP

CT60

Wang, L [17]

2001

Shandong

40 ± 13

87

84

PCR-PFLP

+49A/G

Wang, P W [18]

2007

Taiwan

39 ± 13

208

192

PCR-RFLP

+49A/G, CT60

Wang, Q H [19]

2003

Zhejiang

45.7 ± 9.5

64

28

PCR-PFLP

+49A/G

Wang, S Q [20]

2010

Shandong

41.5 ± 28.5

90

90

PCR-PFLP

+49A/G

Weng, Y C [21]

2005

Taiwan

34.0 ± 11.8

107

101

PCR-PFLP

+49A/G

Yang, J [22]

2012

Xi’an

34.14 ± 12.23

303

215

PCR-PFLP

+49A/G

Yao, B [23]

2005

Guangdong

36.6 ± 12.8

120

123

PCR-PFLP,

PCR-SSLP

+49A/G

Yu, Q L [24]

2006

Guangdong

45 ± 11

100

100

PCR-PFLP

+49A/G

Yu, Z Y [25]

2008

Xi’an

36.7 ± 13.28

125

126

PCR-RFLP

+49A/G

Zhang, H [26]

2010

Shandong

-

211

85

PCR-PFLP

−318C/T

Zhang, J L [27]

2008

Shandong

37.8 ± 13.3

186

100

PCR-PFLP

+49A/G

Zhang, Q [28]

2006

Zhejiang

-

89

60

PCR-RFLP

+49A/G, -318C/T

Zhao, S X [5]

2010

Shandong, Suzhou, Guangdong, Fujian

-

2640

2204

Mass-Array™

+49A/G

Table 2

Distribution of CTLA-4 genotype among patients with Graves’ disease and controls included in the meta-analysis

Polymorphism

Author

Case

Control

Case

Control

HWE

+49A/G polymorphism

 

AA

AG

GG

AA

AG

GG

A

G

A

G

 

Du, Y T [11]

1

27

68

7

26

27

29

163

40

80

Yes

Guo, Z Q [12]

24

52

26

41

47

12

100

104

129

71

Yes

Han, S Z [2]

33

95

135

32

89

75

161

365

153

239

Yes

Jiang, B R [13]

10

44

44

33

46

16

64

132

112

78

Yes

Shen, F X [15]

5

34

68

4

30

23

44

170

38

76

Yes

Wang, L [17]

3

47

37

32

42

10

53

121

106

62

Yes

Wang, P W [18]

15

69

124

18

77

97

99

317

113

271

Yes

Wang, Q H [19]

21

24

19

12

15

1

66

62

39

17

Yes

Weng, Y C [21]

8

53

46

15

58

28

69

145

88

114

Yes

Wang, S Q [20]

5

47

38

24

52

14

57

123

100

80

Yes

Yang, J [22]

12

139

152

29

97

89

163

443

155

275

Yes

Yao, B [23]

9

53

58

11

57

55

71

169

79

167

Yes

Yu, Q L [24]

13

36

51

28

46

26

62

138

102

98

Yes

Yu, Z Y [25]

13

45

67

20

60

46

71

179

100

152

Yes

Zhang, J L [27]

16

100

70

32

43

25

132

240

107

93

Yes

Zhang, Q [28]

2

29

58

7

26

27

33

145

40

80

Yes

Zhao, S X [5]

104

730

1030

156

823

945

938

2790

1135

2713

Yes

−318C/T polymorphism

 

CC

CT

TT

CC

CT

TT

C

T

C

T

 

Chong, K K [10]

147

28

2

122

29

0

322

32

273

29

Yes

Du, Y T [11]

80

13

3

46

12

2

173

19

104

16

Yes

Guo, Z Q [12]

84

18

0

76

23

1

186

18

175

25

Yes

Kang, Y Z [14]

52

8

1

48

11

1

112

10

107

13

Yes

Zhang, H [26]

175

35

1

69

16

0

385

37

154

16

Yes

Han, S Z [2]

159

98

2

103

85

2

416

26

291

101

Yes

Zhang, Q [28]

65

22

6

46

12

8

152

110

104

16

Yes

CT60 polymorphism

 

GG

AG

AA

GG

AG

AA

G

A

G

A

 

Chong, K K [10]

125

48

4

88

51

12

298

56

227

75

Yes

Han, S Z [2]

184

71

8

123

60

13

439

87

306

86

Yes

Tsai, S T [16]

136

48

5

372

216

32

320

58

960

280

Yes

 

Wang, P W [18]

138

46

5

125

58

9

322

56

308

76

Yes

Quantitative synthesis

The +49A/G polymorphism

A total of 4009 cases and 3651 controls from 17 case–control studies were included for data synthesis. As is shown in Figure 1, we analyzed the heterogeneity of GG+GA vs. AA for all 17 studies and the value of X 2 was 47.22 with 16 degrees of freedom and p-value < 0.00001 in a random-effects model. Additionally, I-square value is another index of the test of heterogeneity. In Figure 1, the I-square was 66.1%, suggesting a moderate of heterogeneity. Thus, we chose the random-effects model to synthesize the data. Overall, OR was 2.57 (95%CI = 1.87-3.52) and the test for overall effect Z value was 5.83 (p-value < 0.00001). The results suggested that the G allele carriers might have an increased risk of Graves’ disease compared with those individuals with the AA homozygote. Statistically similar results were obtained after sequential excluding each case–control study for the GG+GA vs. AA comparative, suggesting the stability of our meta-analysis. Significant publication bias was detected in the funnel plot (figure not shown), and in the Egger’s test, the result was: t = 2.82, p-value = 0.013, which also indicated considerable publication bias. Summary of the results of other genetic comparisons are listed in Table 3.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2350-14-46/MediaObjects/12881_2012_Article_1073_Fig1_HTML.jpg
Figure 1

Meta-analysis with a random-effects model for the association between GD risk and the CTLA-4 +49A/G polymorphism (GG+GA vs. AA).

Table 3

Summary of different comparative results

Polymorphism

Genetic model

Participants

OR (95%CI)

Z

p-value

I2, %

P Het

Effect model

+49A/G

GG+GA vs. AA

7660

2.57(1.87,3.52)

5.83

< 0.00001

66.1

< 0.0001

Random

 

GG vs. GA+AA

7660

2.11(1.70,2.63)

6.69

< 0.00001

70.3

< 0.00001

Random

 

GG vs. AA

4402

3.87(2.59,5.80)

6.57

< 0.00001

74.3

< 0.00001

Random

 

GA vs. AA

4053

1.96(1.44,2.67)

4.25

< 0.00001

60.8

0.0006

Random

 

G vs. A

15320

1.88(1.58,2.23)

7.18

< 0.00001

76.8

< 0.00001

Random

−318C/T

TT+TC vs. CC

1701

0.78(0.62,0.97)

2.18

0.03

0

0.86

Fixed

 

TT vs. TC+CC

1701

0.76(0.37,1.53)

0.78

0.44

0

0.92

Fixed

 

TT vs. CC

1291

0.70(0.35,1.43)

0.97

0.33

0

0.90

Fixed

 

TC vs. CC

1672

0.78(0.62,0.98)

2.11

0.03

0

0.86

Fixed

 

T vs. C

3402

0.80(0.66,0.98)

2.12

0.03

0

0.88

Fixed

CT60 G/A

AA + AG vs. GG

1977

0.64(0.52,0.78)

4.34

< 0.0001

0

0.82

Fixed

 

AA vs. AG + GG

1977

0.43(0.26,0.72)

3.22

0.001

0

0.82

Fixed

 

AA vs. GG

1379

0.39(0.23,0.65)

3.62

0.0003

0

0.81

Fixed

 

AG vs. GG

1889

0.69(0.55,0.85)

3.52

0.0004

0

0.82

Fixed

 

A vs. G

3954

0.65(0.54,0.77)

4.9

< 0.00001

0

0.81

Fixed

The -318C/T polymorphism

A total of 999 cases and 702 controls from 7 case–control studies were included for data synthesis. As is shown in Figure 2, we analyzed the heterogeneity of TT+TC vs. CC for all 7 studies and the value of X 2 was 2.56 with 6 degrees of freedom and p-value = −0.86 in a fixed-effects model. Additionally, I-square value is another index of the test of heterogeneity. In Figure 2, the I-square was 0%, suggesting an absent of heterogeneity. Thus, we chose the fixed-effects model to synthesize the data. Overall, OR was 0.78 (95%CI = 0.62-0.97) and the test for overall effect Z value was 2.18 (p-value = 0.03). The results suggested that the T allele carriers might have a decreased risk of Graves’ disease compared with those individuals with the CC homozygote. Statistically similar results were obtained after sequential excluding each case–control study for the TT+TC vs. CC comparative, suggesting the stability of our meta-analysis. No publication bias was detected with either the funnel plot (figure not shown) or Egger’s test (t = 0.09, p-value = 0.929). Summary of the results of other genetic comparisons are listed in Table 3.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2350-14-46/MediaObjects/12881_2012_Article_1073_Fig2_HTML.jpg
Figure 2

Meta-analysis with a random-effects model for the association between GD risk and the CTLA-4 -318C/T polymorphism (TT+TC vs. CC).

The CT60 polymorphism

A total of 818 cases and 1159 controls from 4 case–control studies were included for data synthesis. As is shown in Figure 3, we analyzed the heterogeneity of AA+AG vs. GG for all 4 studies and the value of X 2 was 0.91 with 3 degrees of freedom and p-value = 0.82 in a fixed-effects model. Additionally, I-square value is another index of the test of heterogeneity. In Figure 3, the I-square was 0%, suggesting an absent of heterogeneity. Thus, we chose the fixed-effects model to synthesize the data. Overall, OR was 0.64 (95%CI = 0.52-0.78) and the test for overall effect Z value was 4.34 (p-value = 0.001). The results suggested that the A allele carriers might have a decreased risk of Graves’ disease compared with those individuals with the GG homozygote. Statistically similar results were obtained after sequential excluding each case–control study for the AA+AG vs. GG comparative, suggesting the stability of our meta-analysis. No publication bias was detected with either the funnel plot (figure not shown) or Egger’s test (t = 0.19, p-value = 0.864). Summary of the results of other genetic comparisons are listed in Table 3.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2350-14-46/MediaObjects/12881_2012_Article_1073_Fig3_HTML.jpg
Figure 3

Meta-analysis with a random-effects model for the association between GD risk and the CTLA-4 CT60 polymorphism (AA+AG vs. GG).

Discussion

Graves' disease (GD) is a thyroid-specific autoimmune disease affecting 0.25–1.09% of the Chinese population [2]. To this day, the mechanisms of GD have been widely studied from the environmental factors to the genetic factors [29]. However, the results are inconsistent and the exact mechanisms are still unrevealed. Among genetic risk factors, the cytotoxic T lymphocyte associated-4 (CTLA-4) gene is one of the widely investigated. CTLA-4 gene, which encodes a vital negative regulatory molecule of the immune system [30], has been demonstrated as candidate gene of GD [31, 32]. To date, three polymorphisms (+49A/G, -318C/T and CT60) have been suggested as GD risk factors in the Chinese population. However, the results were inconsistent. Therefore, we performed a comprehensive meta-analysis to assess the association and to get more conclusive results.

This meta-analysis, including a total of 28 case–control studies in 21 publications, investigated three most widely studied polymorphisms in the CTLA-4 gene. We found that the +49A/G polymorphism was associated with an increased risk of GD in the Chinese population, and the G allele carriers might have a higher risk of disease than the AA homozygote carriers. The results suggested a significant association between this polymorphism in the Chinese population, which is consistent with some other populations, such as the UK population [33] and the Iranian population [34]. Our results indicated that the increase in the risk is more evident in the Chinese population than in other populations, suggesting possible roles of ethnic differences in genetic backgrounds and the environment. In addition, the +49A/G polymorphism is located in exon 1, and results in a threonine-to-alanine conversion at codon 17 in the peptide leader sequence of the CTLA-4 protein. It reported that this polymorphism was associated with lower mRNA levels of the soluble alternative splice form of CTLA-4 [35]. Thus, our results could be partly explained that the variant carriers might have lower mRNA levels of the protein of the CTLA-4, and then have increased risk of the disease. In future, more studies should be performed in the Chinese population to validate these results.

A total of 999 cases and 702 controls from 7 case–control studies were included for the -318C/T polymorphism. The results suggested that the T allele carriers might be associated with a decreased risk of GD compared with CC homozygote carriers. As for the CT60 polymorphism, 818 cases and 1159 controls from 4 case–control studies were included, and the results also indicated a decrease in the risk of GD. Considering the included case–control studies for both polymorphisms were relatively small, larger number of relevant studies are needed in future to validate these results.

Hitherto, many studies have already been published focusing on the genetic risk factors of the GD among the Chinese population. For instance, Chu reported that a non-synonymous single-nucleotide polymorphism rs40401 (P27S) of the interleukin 3 (IL3) gene was associated with increased risk of GD [36]; Guo found the rs568408 polymorphism in the interleukin-12 (IL-12) gene was also associated with increased risk of GD [37]. In addition, polymorphisms in the ADRB2 gene [3], interleukin-10 (IL-10) gene [38], TNF-α gene [39] were also found to be associated with GD in Chinese population. These genes were all suggested as the candidate genes for GD in Chinese population. In future, the associations between these polymorphisms and the GD risk in Chinese population are needed to be validated by more case–control studies.

In the present meta-analysis, sensitivity analysis was performed and stability of the results was guaranteed. Publication bias was assessed by Begg’s funnel plot and Egger’s test [40]. No significant publication bias was found for the -318C/T and the CT60 polymorphism analysis, suggesting the results of these two polymorphisms were more reliable. However, we found significant publication bias for the +49A/G polymorphism. The reason might be that some reports were not published, especially for those with negative results. The results might affect the strength of the association, thus, large scale case–control studies are needed to assess the association between the +49A/G polymorphism and GD risk.

We have to mention the heterogeneity. We found significant heterogeneity for the +49A/G polymorphism. Since all participants were Chinese, the genetic background might not be taken as a factor for the heterogeneity for +49A/G polymorphism. However, some other factors, such as gender, age and location might affect the heterogeneity. In addition, we found no heterogeneity for the -318C/T and the CT60 polymorphisms, which suggested that the association for these two polymorphisms are more reliable than the +49A/G polymorphism.

It is reported that GD occurs more frequently but less severe in women than in men. In China, the different condition of disease in men and women might be similar to the situation of the world. In our study, the data was not analyzed by gender because of the lack of original information for these populations. In future, such subgroup studies are also needed to be carried out. Moreover, the cases and controls in this meta-analysis were mostly based on Han nationality, but not in the minorities. In order to get comprehensive results of the Chinese population, studies based on the minorities are also needed.

There are several limitations in this meta-analysis. First, the quantity of enrolled published studies was not very ideal, especially for the -318C/T and CT60 polymorphism. This might cause some potential publication bias, although the results of the above mentioned bias tests was not significant for these two polymorphisms. Second, data were not stratified into subgroups according to some other factors such as age, gender, location and ethnicity (Han or others), due to the lack of information in the original studies. Third, the interactions between genetic factors and environmental factors were not discussed for these three polymorphisms. Fourth, the current meta-analysis only investigated the three most widely studied polymorphisms, and some other polymorphisms with fewer reports were not included. And in future, if there were more case–control studies, new meta-analysis should be conducted. Despite of these limitations, we have minimized the bias through the whole process based on means in study identification, data selection and statistical analysis as well as in the control of publication bias and sensitivity, and got a more reliable result.

Conclusions

To our knowledge, this is the first comprehensive genetic meta-analysis performed in Chinese population for Graves’ disease and CTLA-4 gene. We found that three polymorphisms (+49A/G, -318C/T and CT60) in the CTLA-4 gene were associated with the risk of GD. Our results supported the classic view that GD is associated with heredity and revealed that genes in the pathogenesis are important for GD. These results may have implications for further medicine researches about GD for the Chinese population. In future, more large-scale case–control studies are needed to validate our results.

Declarations

Acknowledgements

This study was supported by grants 81101939 from National Natural Science Foundation of China.

Authors’ Affiliations

(1)
West China Medical School/West China Hospital, Sichuan University
(2)
The Periodical Press of West China Hospital, Sichuan University

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  41. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/14/46/prepub

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