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

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.

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.

• References

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