Horm Metab Res 2020; 52(01): 67-70
DOI: 10.1055/a-1063-6377
Letter to the Editor
© Georg Thieme Verlag KG Stuttgart · New York

Update on “Associations of Estrogen Receptor Alpha Gene Polymorphisms with Type 2 Diabetes Mellitus and Metabolic Syndrome: A Systematic Review and Meta-Analysis”

Zulvikar Syambani Ulhaq
Further Information

Publication History

Publication Date:
16 January 2020 (online)

Dear Editor,

Associations of Estrogen Receptor Alpha Gene Polymorphisms with Type 2 Diabetes Mellitus and Metabolic Syndrome: A Systematic Review and Meta-Analysis

Yang et al. [1] published a meta-analysis on the association of ESR1 (estrogen receptor alpha) polymorphism and the risk of type 2 diabetes mellitus (T2DM). Based on to their findings, recessive model ESR1 rs2234693 polymorphism (OR=0.673, 95 % CI=0.550–0.823, p random-effect model<0.001, p fixed-effect model<0.003) was significantly associated with the susceptibility to T2DM.

However, there are some mistype on the genetic models, it should be written recessive model rather than the regressive model in the manuscript. Moreover, in this letter, I also update the results of the meta-analysis for the association between ESR1 polymorphisms with T2DM. In this present study, two studies published by Akhmad et al. [2] and Ereqat et al. [3] are included ([Table 1]). It showed that no associations were observed between ESR1 rs2234693 or rs9340799 polymorphisms with T2DM ([Tables 2] and [3]). However, when the two studies from ESR1 rs2234693 in which the genotype distribution for the control groups deviated from HWE were excluded, a significant association was observed in the homozygous model (CC vs. TT, OR=0.64; 95% CI 0.47–0.88, p=0.006, I2=39.15%) ([Table 2], [Fig. 1]). No change was observed from ESR1 rs9340799, although three studies deviated from HWE were excluded ([Table 3]). No publication bias was observed among studies (p>0.05, data now shown). Together, these results suggest that homozygous of CC genotype ESR1 rs2234693 shows a protective effect against T2DM. Indeed, the estrogen receptor and its signaling play an important role in regulating insulin sensitivity [4]. Nevertheless, more studies, especially for ESR1 rs2234693, are needed to verify these results.

Zoom Image
Fig. 1 Association of homozygous model (CC vs. TT) in ESR1 rs2234693 polymorphism with T2DM.

Table 1 Characteristics of individual studies for association between ESR1 polymorphisms and T2DM.

rs2234693 (PvuII)

No.

Author [Ref]

Year

Country

Sample size (T2DM/Control)

Genotype distribution T2DM

Control

PHWE *

Allele distribution T2DM

Control

TT

TC

CC

TT

TC

CC

T

C

T

C

1

Akhmad et al. [2]

2013

Indonesia

40/25

9

18

13

4

14

4

0.2008

44

36

22

28

2

Chen et al. [5]

2015

China

20/40

4

10

6

4

25

11

0.0671

18

22

33

47

3

Dong et al. [6]

2002

China

104/60

16

62

25

7

26

27

0.8465

95

113

40

80

4

Ereqat et al. [3]

2019

Palestine

102/112

27

57

18

43

47

22

0.1685

111

93

133

91

5

Ganasyam et al. [7]

2012

India

100/100

39

43

18

52

32

16

0.0081

121

79

136

64

6

Huang et al. [8]

2006

China

299/341

36

172

91

34

149

158

0.8962

224

354

217

465

7

Meshkani et al. [9]

2012

Iran

152/299

52

73

27

64

173

62

0.0065

177

127

301

297

8

Mohammadi et al. [10]

2013

Iran

174/174

50

67

57

25

84

65

0.7981

167

181

134

214

9

Motawi et al. [11]

2015

Egypt

90/40

24

49

17

15

19

6

0.9967

97

83

49

31

rs9340799 (XbaI)

No.

Author [Ref]

Year

Country

Sample size (T2DM/Control)

Genotype distribution T2DM

Control

P HWE *

Allele distribution T2DM

Control

AA

AG

GG

AA

AG

GG

A

G

A

G

1

Akhmad et al. [2]

2013

Indonesia

40/25

4

25

11

18

33

14

0.8767

47

33

61

69

2

Chen et al. [5]

2015

China

20/40

3

5

12

8

25

7

0.1127

11

29

41

39

3

Dong et al. [6]

2002

China

104/60

11

74

19

21

38

1

0.001

96

112

80

40

4

Ereqat et al. [3]

2019

Palestine

102/112

44

44

24

40

101

73

0.6284

132

92

247

118

5

Ganasyam et al. [7]

2012

India

100/100

5

20

75

4

10

86

0.0001

30

170

22

186

6

Huang et al. [8]

2006

China

299/341

33

149

117

33

158

150

0.3526

383

215

458

214

7

Meshkani et al. [9]

2012

Iran

152/299

57

68

27

76

167

56

0.0348

182

122

319

279

8

Mohammadi et al. [10]

2013

Iran

174/174

53

60

61

24

77

73

0.6096

166

182

125

223

9

Motawi et al. [11]

2015

Egypt

90/40

34

39

17

20

15

5

0.4209

55

25

107

73

10

Speer et al. [12]

2001

Hungary

49/138

22

25

2

20

88

30

0.0009

69

29

128

148

* p-Values for Hardy–Weinberg equilibrium test in controls.

Table 2 Meta-analysis for the association between ESR1 rs2234693 (PvuII) polymorphism and T2DM.

All relevant articles were included (n=9)

Contrast

Test of association

Model*

Test of heterogeneity

OR

95% CI

p

p

I2 (%)

C vs. T

0.88

[0.70; 1.09]

0.26

Random

0.0056

63.08

CC vs. CT+TT

0.78

[0.58; 1.04]

0.09

Random

0.0632

45.94

CC+CT vs. TT

0.87

[0.57; 1.31]

0.51

Random

0.0008

70.03

CC vs. TT

0.73

[0.50; 1.07]

0.11

Random

0.0712

44.56

CT vs. TT

0.92

[0.59; 1.44]

0.73

Random

0.0005

71.20

Articles deviated for HWE were excluded (n=7)

Contrast

Test of association

Model *

Test of heterogeneity

OR

95% CI

p

p

I2 (%)

C vs. T

0.85

[0.66; 1.09]

0.21

Random

0.0257

58.26

CC vs. CT+TT

0.74

[0.51; 1.07]

0.11

Random

0.0558

51.19

CC+CT vs. TT

0.85

[0.53; 1.37]

0.51

Random

0.013

62.85

CC vs. TT

0.64

[0.47; 0.88]

0.006

Fixed

0.1307

39.15

CT vs. TT

0.92

[0.55; 1.55]

0.76

Random

0.0082

65.32

* If the p-value for Q-statistic was<0.10 or the I2 value ≥50%, random-effect model was used, otherwise fixed-effect model was adopted.

Table 3 Meta-analysis for the association between ESR1 rs9340799 (XbaI) polymorphism and T2DM.

All relevant articles were included (n=10)

Contrast

Test of association

Model*

Test of heterogeneity

OR

95% CI

p

p

I2 (%)

G vs. A

0.91

[0.65; 1.27]

0.604

Random

0.0001

85.36

GG vs. TC+CC

0.94

[0.62; 1.43]

0.794

Random

0.0002

72.04

GG+AG vs. AA

0.84

[0.48; 1.46]

0.541

Random

0.0001

84.24

GG vs. AA

0.89

[0.45; 1.73]

0.738

Random

0.0001

81.03

GA vs. AA

0.82

[0.48; 1.40]

0.479

Random

0.0001

80.20

Articles deviated for HWE were excluded (n=7)

Contrast

Test of association

Model*

Test of heterogeneity

OR

95% CI

p

p

I2 (%)

G vs A

0.93

[0.68; 1.28]

0.688

Random

0.0001

80.21

GG vs. TC+CC

1.00

[0.67; 1.47]

0.993

Random

0.0065

66.48

GG+AG vs. AA

0.77

[0.46; 1.29]

0.335

Random

0.0002

76.98

GG vs. AA

0.85

[0.46; 1.55]

0.608

Random

0.0004

75.91

GA vs. AA

0.72

[0.44; 1.18]

0.198

Random

0.0017

71.77

* If the p-value for Q-statistic was<0.10 or the I2 value ≥ 50%, random-effect model was used, otherwise fixed-effect model was adopted.