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Association between polymorphisms in the estrogen receptor alpha gene and osteoarthritis susceptibility: a meta-analysis

Contributed equally
BMC Musculoskeletal Disorders201516:44

https://doi.org/10.1186/s12891-015-0506-5

Received: 16 September 2014

Accepted: 19 February 2015

Published: 27 February 2015

Abstract

Background

Osteoarthritis (OA) is a common chronic disease of the joints. Genetic factors may play a role in its development, and polymorphisms in the estrogen receptor alpha gene (ERα) have been associated with OA. However, previous studies into this relationship have reported inconsistent results, so we aimed to systematically review the association between ERα polymorphisms and OA susceptibility.

Methods

We conducted a comprehensive literature search of Ovid MEDLINE, EMBASE, CBM, and PubMed databases, and Google scholar, and identified 11 eligible studies that examined the association between ERα polymorphisms and OA susceptibility. We carried out a meta-analysis of these studies based on ERα XbaI (rs9340799) and PvuII (rs2234693) genotypes.

Results

Seventeen comparisons involving 10 European and seven Asian populations of 5,325 OA patients and 10,834 controls were included in the study. The ERα XbaI polymorphism were significantly associated with OA in Europeans (AA vs. AG + GG: OR = 1.17, 95% confidence interval (CI) = 1.02–1.34, P = 0.03; AG vs. AA + GG: OR = 0.86, 95% CI = 0.75–0.99, P = 0.04) but not in Asian populations. No association was found between OA and the ERα PvuII polymorphism in any population (C vs. T, OR = 0.98, 95% CI = 0.93–1.03, P = 0.37; CC vs. TT + CT, OR = 0.97, 95% CI = 0.89–1.06, P = 0.55; CT vs. CC + TT, OR = 0.99, 95% CI = 0.92–1.06, P = 0.75; TT vs. CC + CT, OR = 1.01, 95% CI =0.92–1.12, P = 0.79).

Conclusions

This study suggested that there may be a weak relationship between the ERα XbaI polymorphism and OA in Europeans but not Asians, and that the ERα PvuII polymorphism was not associated with OA in either population. However, large well-designed studies are necessary to confirm these results in more homogeneous populations.

Keywords

Estrogen receptor Osteoarthritis Polymorphism Meta-analysis

Background

Osteoarthritis (OA) is the most common joint disease worldwide, and primarily affects the knees, hips, hands, and spine. It is a leading cause of disability among older individuals and also affects their quality of life [1]. It is characterized by the progressive degeneration of articular cartilage, and by subchondral sclerosis resulting in pain and joint stiffness [2].

The etiology of OA is multifactorial, including genetic and environmental risk factors. Associated genes include GDF5 [3], ASPN [4], FRZB [5], and COL2A1 [6], while environmental factors may include obesity [7-9], history of knee injury [10], occupational activities [11,12], sex hormones and structural changes [13], meniscectomy [14], gender, and age [15]. Twin-pair and family genetic data show that more than 50% of OA can be attributed to genetic factors [16]. A gender difference is also apparent, with females having a greater prevalence of OA after the age of 50 years [17]. Additionally, the disease is more common among European populations [18]. The observation that the estrogen receptor (ER) is expressed in human articular chondrocytes and bone cells suggests that it may be involved in the etiology of OA [19].

The ER has two isoforms: ERα and ERβ. ERα expression affects the growth of bone cells, while ERβ participates in the formation and resorption of bone [20]. ERα is located on chromosome 6q25.1 and contains eight exons and seven introns [21], as well as two common restriction fragment length polymorphisms (RFLPs): XbaI and PvuII. The XbaI RFLP detects an A–G substitution at position 351 (−351int A/G; rs9340799), while PvuII detects a T–C substitution at position 397 (−397int T/C; rs2234693). A previous meta-analysis confirmed the association between bone mineral density and ERα [22].

A number of studies have investigated the association between ERα polymorphisms and the risk of OA in different populations, but the results are inconsistent. Some discovered that ERα polymorphisms were associated with an increased risk of OA [23-28], while others found no association with OA risk [28,29], or an association with a reduced risk of OA [30-34]. To our knowledge, no systematic review has examined the evidence for a relationship between ERα polymorphisms and OA. Therefore, we conducted a meta-analysis to analyze the association between ERα polymorphisms and OA susceptibility.

Methods

This systematic review was conducted according to 2009 PRISMA guidelines [35].

Search strategy

We performed a systematic research of available studies that assessed the association between ERα polymorphisms and OA. We carried out a comprehensive literature search for published studies in OVID MEDLINE, EMBASE, CBM, and PubMed databases, and Google Scholar. Primary key search terms included estrogen receptor, polymorphism, osteoarthritis, and OA. Index terms for OVID MEDLINE were: “estrogen receptor”, “polymorphism”, and “osteoarthritis” or “OA”. The last query was updated on 30 November 2014. There were no language or other limitations on the search. Reference lists in the retrieved articles or relevant reviews were also screened to identify other eligible studies. We also searched unpublished studies by contacting clinical experts and the Arthritis Foundation National Office. A flow diagram of our literature identification strategy is shown in Figure 1.
Figure 1

Flow diagram of study selection according to the PRISMA statement.

Inclusion and exclusion criteria

Eligible studies were required to satisfy the following criteria: (1) the study was a cohort or a case–control study; (2) OA was diagnosed based on clinical criteria defined by the American College of Rheumatology; (3) the original study assessed the association between ERα polymorphisms (XbaI or PvuII) and OA susceptibility; and (4) the study provided sufficient genetic frequency or sufficient data for extraction. If overlapping study populations were identified between studies, only the most complete one was included in the meta-analysis. Animal studies and literature reviews were excluded.

Quality assessment of included studies

Study quality was independently assessed by two authors, based on the Newcastle–Ottawa scale (NOS) quality score systems [36]. The NOS contains eight items divided into three categories: selection, comparability, and outcome (for cohort studies) or exposure (for case–control studies). Quality scores ranged from 0 to 9. When there was disagreement on the quality scores between the two authors, discrepancies were resolved through discussion and consultation with a third author.

The quality of included studies was also assessed by the Hardy–Weinberg equilibrium (HWE) for the control genotype distribution. Studies consistent with HWE were defined as high-quality, while those inconsistent with HWE were defined as low-quality studies.

Data extraction

The following data were extracted from each full-text study using a standardized data extraction form: the name of the first author, year of publication, country in which the study was performed, study design, number of cases and controls, gender, age, genotyping, OA site, OA definition, polymorphism, and numbers of cases and controls for each of the PvuII (rs2234693), and XbaI (rs9340799) genotypes. When the information extracted from studies was inconsistent, disagreement was resolved through discussion and consultation with a third author until consensus was achieved on every item.

Statistical analysis

STATA 12.0 and Review Manager 5.2 software were used for data analysis. The pooled odds ratio (OR) and its 95% confidence interval (95% CI) were calculated to assess the association between ERα polymorphisms and the risk of OA for the following contrasts: G vs. A, AG vs. AA + GG, GG vs. AG + AA, AA vs. AG + GG, C vs. T, CC vs. TT + CT, CT vs. CC + TT, and TT vs. CC + CT. Subgroup analysis based on ethnicity was also performed. The Chi-square test was used to determine if the identified study was consistent with HWE for the control genotype distribution. Heterogeneity between studies was evaluated with the I2 test and the Q statistic. We used the Cochrane system for heterogeneity grading: I2 0–40%, might not be important; 30–60%, moderate heterogeneity; 50–90%, substantial heterogeneity; 75–100%, considerable heterogeneity. Heterogeneity was assessed to be significant when I2 > 30% or when P < 0.1 for Q statistics.

The pooled effects were estimated using the Der-Simonian and Laird method for random effects and the Mantel–Haenszel method for fixed effects [37]. If the studies were significantly heterogeneous, we used the random effects model. Otherwise, we used the fixed effects model to calculate the pooled OR and 95%CI. The random effects model assumes that different studies have substantial diversity and assesses both within-study sampling error and between-study variation [38]. The fixed effects model assumes that genetic factors have similar effects on OA susceptibility across all studies, and that observed variations between studies are caused by chance alone [39]. Sensitivity analyses were performed for the effect size omitting the trial for which data were imputed, and were used to evaluate the stability of the results. Publication bias was graphically represented by funnel plots and further evaluated with the Begg’s test and Egger’s test [40,41].

Results

Search results and studies included in the meta-analysis

Seventy-seven relevant studies were preliminarily identified in the database search, of which 11 [24-34] eventually satisfied the eligibility criteria for our meta-analysis. All included studies investigated the relationship between ERα polymorphisms and OA susceptibility. Of these, one study [33] contained data on three different OA sites and four different geographical locations, so these seven comparisons were treated independently. Therefore, a total of 17 separate comparisons were included in the present meta-analysis. Ten studies with a total of 8,502 participants (2,181 OA patients and 6,321 controls), which involved three European and seven Asian populations, evaluated the association between the ERα XbaI polymorphism and OA susceptibility, while 17 with 16,159 total participants (5,325 OA patients and 10,834 controls), involving 10 European and seven Asian populations, evaluated the association between the ERα PvuII polymorphism and OA susceptibility. Study characteristics are summarized in Table 1.
Table 1

Characteristics of the included studies

Study [Ref.]

Year

Country (City)

Study design

Genotyping

Numbers

Gender (M/F)

Age

Polymorphism (s)

Quality score

OA

Control

OA

Control

OA

Control

  

Toshio Ushiyama et al. [24]

1998

Japan

Case–control

PCR

65

318

0/65

0/318

68.5 (49–86)

49-86

XbaI, PvuII

7 (2/2/3)

John Loughlin et al. [29]

2000

UK (Oxford)

Case–control

PCR

371

369

155/216

221/148

73 (56–90)

73 (59–89)

XbaI, PvuII

8 (3/2/3)

Barton L. Wise et al. [30]

2009

USA

Cohort

PCR

307

214

258/263

61 ± 9

XbaI

8 (4/2/2)

Barton L. Wise et al. [30]

2009

USA

Cohort

PCR

304

211

253/262

61 ± 9

PvuII

V. M. Borgonio-Cuadra et al. [32]

2012

Mexico

Case–control

PCR

115

117

23/92

20/97

57.4 ± 9.2

51.8 ± 8.9

XbaI, PvuII

9 (4/2/3)

J. A. Riancho et al. [33]

2010

Spain (Santander)

Case–control

PCR

272

802

95/177

285/517

72 ± 7

71 ± 10

PvuII

8 (3/2/3)

J. A. Riancho et al. [33]

2010

Spain (Santiago)

Case–control

PCR

254

473

47/207

295/178

68 ± 6

68 ± 9

PvuII

J. A. Riancho et al. [33]

2010

UK (Oxford)

Case–control

PCR

445

862

176/269

471/391

64 ± 5

69 ± 7

PvuII

J. A. Riancho et al. [33]

2010

Spain (Santander)

Case–control

PCR

359

802

180/179

285/517

71 ± 7

71 ± 10

PvuII

J. A. Riancho et al. [33]

2010

Spain (Coruña)

Case–control

PCR

252

244

90/162

97/147

67 ± 14

65 ± 13

PvuII

J. A. Riancho et al. [33]

2010

Spain (Santiago)

Case–control

PCR

287

473

110/177

295/178

68 ± 5

68 ± 9

PvuII

J. A. Riancho et al. [33]

2010

UK (Oxford)

Case–control

PCR

1278

862

503/775

471/391

65 ± 6

69 ± 7

PvuII

K. Lian M.D. et al. [31]

2007

USA

Cohort

PCR

569

4134

0/569

0/4134

79.6 ± 5.0

78.4 ± 4.6

XbaI, PvuII

8 (4/2/2)

Sheng-Yu Jin et al. [25]

2004

Korea

Case–control

PCR

151

397

53/98

190/207

58.8 ± 9.6

/

XbaI, PvuII

8 (3/2/3)

Zhi Tian et al. [28]

2009

China

Case–control

PCR

38

40

0/38

0/40

59.2 ± 3.2

58.5 ± 8.6

XbaI, PvuII

7 (2/2/3)

Jiexiang Yang et al. [34]

2009

China

Case–control

PCR

41

40

31/50

54.6 (28–82)

XbaI, PvuII

6 (2/1/3)

Yan Xue et al. [27]

2004

China

Case–control

PCR

55

176

0/55

0/176

58.7 ± 2.4

60 ± 10

XbaI, PvuII

7 (3/1/3)

Xiaoyu Dai et al. [26]

2014

China

Case–control

PCR

469

522

113/356

398/124

57.3 ± 10.9

56.4 ± 9.8

XbaI, PvuII

7 (3/1/3)

Allele and genotype counts

Allelic counts of the ERα XbaI polymorphism were evaluated for G and A alleles. In general, the frequency of the A allele was higher in OA cases than in controls. Genotype counts of the ERα XbaI polymorphism were evaluated for GG, AG, and AA genotypes, and the frequency of the AA genotype was higher in OA cases than in the control group in all but one study [24]. The frequency of the AG genotype was lower in OA cases than in the control group in all but the same study [24]. There was no obvious difference in the frequency of the GG genotype between OA cases and controls. Allele and genotype counts for the ERα XbaI polymorphism in cases and controls are shown in Table 2.
Table 2

Genotype and allele counts for the ERα Xba I polymorphism in the included studies

Group

Study

Country

OA site

X (G)

x (A)

xx (AA)

Xx (AG)

XX (GG)

    

OA

Control

OA

Control

OA

Control

OA

Control

OA

Control

European

Barton L. Wise et al.

USA

Hand

202

159

412

269

148

85

116

99

43

30

John Loughlin et al.

UK

Hip,Knee

256

251

486

487

164

161

158

165

49

43

K. Lian M.D. et al.

USA

Hip

374

2914

764

5332

257

1700

250

1932

62

491

European Total

   

832

3324

1662

6088

569

1946

524

2196

154

564

Asian

Sheng-Yu Jin et al.

Korea

Knee

57

156

245

638

98

256

49

126

4

15

Toshio Ushiyama et al.

Japan

Hand

30

116

100

520

36

211

28

98

1

9

V. M. Borgonio-Cuadra et al.

Mexico

Knee

49

63

181

171

70

62

41

47

4

8

 

Zhi Tian et al.

China

Knee

24

47

52

33

18

6

16

21

4

13

 

Jiexiang Yang et al.

China

Knee

15

19

67

61

28

24

11

13

2

3

 

Yan Xue et al.

China

Knee

44

200

66

162

21

40

24

82

10

54

 

Xiaoyu Dai et al.

China

Knee

210

193

728

851

288

348

152

155

29

19

Asian Total

   

429

794

1439

2436

559

947

321

542

54

121

Total

   

1261

4118

3101

8524

1128

2893

845

2738

208

685

Allelic counts of the ERα PvuII polymorphism were evaluated for C and T alleles. In general the T allele frequency was higher in OA cases than in the control group. Genotype counts of the ERα PvuII polymorphisms were evaluated for TT, CT, and CC genotypes, and the TT genotype frequency was generally higher in OA cases than in controls. The CC genotype frequency was generally lower in OA cases than controls, although there was no obvious difference in the frequency of the CT genotype between the two groups. Allele and genotype counts for the ERα PvuII polymorphism in cases and controls are shown in Table 3.
Table 3

Genotype and allele counts for the ERα Pvu II polymorphism in the included studies

Group

Study

Coutry (City)

OA site

P (C)

p (T)

pp (TT)

Pp (CT)

PP (CC)

OA

Control

OA

Control

OA

Control

OA

Control

OA

Control

European

Barton L. Wise et al.

USA

Hand

261

192

347

230

101

65

145

100

58

46

J. A. Riancho et al.

Spain (Coruña)

Hip

213

217

291

271

89

76

113

119

50

49

J. A. Riancho et al.

UK (Oxford)

Hip

1109

776

1447

948

426

253

595

442

257

167

J. A. Riancho et al.

UK (Oxford)

Knee

399

776

491

948

123

253

245

442

77

167

J. A. Riancho et al.

Spain (Santander)

Hip

334

752

384

852

105

229

174

394

80

179

J. A. Riancho et al.

Spain (Santander)

Knee

246

752

298

852

79

229

140

394

53

179

J. A. Riancho et al.

Spain (Santiago)

Knee

235

377

273

569

65

176

143

217

46

80

J. A. Riancho et al.

Spain (Santiago)

Hip

239

377

335

569

99

176

137

217

51

80

John Loughlin et al.

UK

Hip,Knee

331

331

411

407

114

110

183

187

74

72

K. Lian M.D et al.

USA

Hip

481

3835

653

4391

188

1162

277

2067

102

884

European Total

   

3848

8385

4930

10037

1389

2729

2152

4579

848

1903

Asian

Sheng-Yu Jin et al.

Korea

Knee

112

307

190

487

61

152

68

183

22

62

Toshio Ushiyama et al.

Japan

Hand

57

260

73

376

19

115

35

146

11

57

V. M. Borgonio-Cuadra et al.

Mexico

Knee

77

82

153

152

52

51

49

50

14

16

 

Zhi Tian et al.

China

Knee

29

34

47

46

16

15

15

16

7

9

 

Jiexiang Yang et al.

China

Knee

37

33

45

47

14

12

17

23

10

5

 

Yan Xue et al.

China

Knee

53

151

57

201

17

57

23

87

15

32

 

Xiaoyu Dai et al.

China

Knee

387

390

551

638

167

198

217

242

85

74

Asian Total

   

752

1257

1116

1947

346

600

424

747

164

255

Total

   

4600

9642

6046

11984

1735

3329

2576

5326

1012

2158

Quality assessment of included studies

All 11 studies had a satisfactory NOS quality score as shown in Table 1. The distribution of genotypes in the controls was in accordance with HWE (P > 0.05) in all studies, so all were classed as high-quality.

Meta-analysis findings

A summary of the meta-analysis findings are shown in Table 4. The ERα XbaI polymorphism was shown not to be associated with OA risk in all populations (G vs. A: OR = 0.87, 95% CI = 0.73–1.04, P = 0.13; AA vs. AG + GG: OR = 1.16, 95% CI =0.94–1.44, P = 0.17; AG vs. AA + GG: OR = 0.93, 95% CI =0.84–1.04, P = 0.22; GG vs. AG + AA: OR = 0.88, 95% CI =0.67–1.17, P = 0.38). However, subgroup analysis by ethnicity showed that the AA and AG genotypes of the ERα XbaI polymorphism were associated with OA risk among Europeans (AA vs. AG + GG: OR = 1.17, 95% CI = 1.02–1.34, P = 0.03; AG vs. AA + GG: OR = 0.86, 95% CI = 0.75–0.99, P = 0.04), but not among Asian populations (Figure 2).
Table 4

Meta-analysis of ERα Xba I and Pvu II polymorphisms and OA susceptibility

Polymorphism comparison

Population OA site

No. of studies

Test of association

Test of heterogeneity

Test of publication bias

Begg's test

Egger's test

OR

95% CI

p-value

Model

Q test

p-value

I 2

Z test

p-value

T test

p-value

XbaI (G vs. A)

Overall

10

0.87

0.73—1.04

0.13

Random

29.71

0.0005

70%

−0.80

0.42

−1.29

0.23

 

European

3

0.91

0.82—1.01

0.08

Fixed

1.67

0.43

0%

    
 

Asian

7

0.80

0.57—1.13

0.21

Random

27.74

0.0001

78%

    

AA vs. AG + GG

Overall

10

1.16

0.94—1.44

0.17

Random

25.55

0.002

65%

1.16

0.25

0.94

0.38

 

European

3

1.17

1.02—1.34

0.03

Fixed

1.91

0.39

0%

    
 

Asian

7

1.22

0.84—1.79

0.30

Random

21.69

0.001

72%

    

AG vs. AA + GG

Overall

10

0.93

0.84—1.04

0.22

Fixed

10.61

0.30

15%

0.09

0.93

0.47

0.65

 

European

3

0.86

0.75—0.99

0.04

Fixed

1.52

0.47

0%

    
 

Asian

7

1.06

0.89—1.26

0.52

Fixed

5.87

0.44

0%

    

GG vs. AG + AA

Overall

10

0.88

0.67—1.17

0.38

Random

14.23

0.11

37%

−0.80

0.42

1.89

0.10

 

European

3

0.97

0.79—1.20

0.81

Fixed

0.85

0.65

0%

    
 

Asian

7

0.65

0.36—1.19

0.17

Random

12.58

0.05

52%

    

PvuII (C vs. T)

Overall

17

0.98

0.93—1.03

0.37

Fixed

19.58

0.24

18%

0.66

0.51

0.87

0.40

 

European

10

0.97

0.90—1.04

0.14

Random

13.61

0.14

34%

    
 

Asian

7

1.07

0.95—1.21

0.25

Fixed

3.19

0.78

0%

    

CC vs. TT + CT

Overall

17

0.97

0.89—1.06

0.55

Fixed

13.09

0.67

0%

0.08

0.93

0.26

0.80

 

European

10

0.94

0.85—1.04

0.21

Fixed

5.05

0.83

0%

    
 

Asian

7

1.17

0.94—1.47

0.16

Fixed

4.94

0.55

0%

    

CT vs. CC + TT

Overall

17

0.99

0.92—1.06

0.75

Fixed

19.85

0.23

19%

0.41

0.68

0.73

0.48

 

European

10

1.01

0.91—1.13

0.82

Random

15.43

0.08

42%

    
 

Asian

7

0.96

0.81—1.14

0.64

Fixed

4.29

0.64

0%

    

TT vs. CC + CT

Overall

17

1.01

0.92—1.12

0.79

Random

23.83

0.09

33%

−0.25

0.81

−1.15

0.27

 

European

10

1.02

0.90—1.17

0.74

Random

20.33

0.02

56%

    
 

Asian

7

0.95

0.80—1.13

0.57

Fixed

2.35

0.88

0%

    
Figure 2

Meta-analysis of the association between the ERα Xba I polymorphism and OA (AG vs. AA + GG).

There was no significant association between the ERα PvuII polymorphism and susceptibility to OA in all populations (C vs. T, OR = 0.98, 95% CI = 0.93–1.03, P = 0.37; CC vs. TT + CT, OR = 0.97, 95% CI = 0.89–1.06, P = 0.55; CT vs. CC + TT, OR = 0.99, 95% CI = 0.92–1.06, P = 0.75; TT vs. CC + CT, OR = 1.01, 95% CI = 0.92–1.12, P = 0.79). In the subgroup analysis based on ethnicity, no significant association was found for the ERα PvuII polymorphism in either European or Asian populations (Figure 3).
Figure 3

Meta-analysis of the association between the ERα Pvu II polymorphism and OA (CC vs. TT + CT).

Sensitivity analysis and publication bias

As shown in Table 4, heterogeneity was observed among studies in all populations and also in subgroup analyses. To explore the sources of heterogeneity across studies we performed a sensitivity analysis, which revealed that none of the studies significantly affected the pooled ORs and CIs. Sequential removal of each study had little effect on the pooled ORs.

The funnel plot revealed no obvious publication bias (Figure 4), and this was confirmed by Begg’s test and Egger’s test.
Figure 4

Funnel plot of the meta-analysis of the ERα PvuII polymorphism with susceptibility to OA (C vs. T).

Discussion

Although the pathogenesis of OA is considered to be the result of many factors, genetics are thought to be one of the most important determinants [42]. Despite the fact that ERα is one of the most studied genes in OA [43], to the best of our knowledge this is the first meta-analysis of the relationship between ERα polymorphisms XbaI and PvuII and OA risk.

Our meta-analysis included 11 published studies (with 17 comparisons) of 16,159 participants (5,325 OA patients and 10,834 controls). Ten studies with a total of 8,502 participants evaluated the association between the ERα XbaI polymorphism and OA susceptibility, and our meta-analysis suggested that it was significantly associated with OA in European but not Asian populations. The pooled OR for homozygote AA carriers showed that they were associated with a 17% increased risk for OA compared with AG and GG carriers, and that European AG carriers had a decreased OA risk. The heterogeneity of genetic effects between European and Asian populations suggests the existence of gene–environment or gene–gene interactions. No heterogeneity was detected in European populations with respect to the ERα XbaI polymorphism and OA, suggesting that the genetic effect of this polymorphism is stronger in European than Asian populations.

Seventeen studies with a total of 16,159 participants evaluated the association between the ERα PvuII polymorphism and OA susceptibility. Our meta-analysis suggested that there was no association between the polymorphism and susceptibility to OA in any population. The same result was obtained for the subgroup analysis based on ethnicity.

Gender differences are known to affect the development of OA; for example, the prevalence of knee OA is greater in women than men [15]. Only two of the studies included in our meta-analysis were stratified according to participant gender [25,32], and both reported no significant differences in the ERα polymorphisms between OA patients and controls of the same sex. However, because of the small number of this type of study and the limited raw data based on gender differences in genotype distributions and allele frequencies, we were unable to perform a subgroup analysis according to gender.

Several limitations should be taken into consideration in the current meta-analysis. First, it was based on unadjusted OR estimates because not all studies presented adjusted ORs, or the ORs were not adjusted by the same potential confounders, such as age and gender. This lack of information could have caused serious confounding bias. Second, OA is influenced by both genetic and environmental risk factors such as obesity, injury, occupational activities, and meniscectomy. However, the studies included in the meta-analysis did not control for these environmental risk factors. Third, some studies included individuals with OA in different sites, but we were unable to perform subgroup analysis of this within the same ethnic population because of the limited available data. For instance, hand OA is known to be more influenced by genetic and hormonal influences than other types of OA, but the relationship between the ERα XbaI polymorphism and hand OA was only reviewed in one study of Europeans [30] and one of Asians [24]. Other studies of the ERα XbaI polymorphism and OA susceptibility in Europeans focused on three different OA sites. Finally, although our current findings suggest that the ERα XbaI polymorphism is associated with OA in Europeans, it was not possible to determine whether this polymorphism is in linkage disequilibrium with any other potentially functional polymorphisms. However, our meta-analysis also had some advantages, including a satisfactory quality of all 11 included studies, and a well-designed method.

Conclusions

The present results suggest that there may be a weak relationship between the ERα XbaI polymorphism and OA in European but not Asian populations, while the ERα PvuII polymorphism did not appear to be associated with OA in either Europeans or Asians. Because the studies included in the meta-analysis reviewed the relationship between the ERα XbaI polymorphism and OA susceptibility at three different sites in Europeans, large well-designed studies are necessary to confirm our findings in more homogeneous populations.

Notes

Declarations

Acknowledgment

This study was supported by grants from the Doctor Foundation of Sichuan Provincial People’s Hospital (30305030575). The authors thank Professor Deiying Kang for advice on modifying the meta-analysis, Min Yang for advice on data analysis, and Bangliang Xiao for logistics support.

Authors’ Affiliations

(1)
Department of Epidemiology and Biostatistics, West China School of Public Health, Sichuan University
(2)
Department of Orthopedics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital
(3)
Department of Preventive Health Care, The People’s Hospital of Dazu District
(4)
Department of Medical Record Management, West China Second University Hospital, Sichuan University

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