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  • Research
  • Open Access

Genetic associations between Transcription Factor 7 Like 2 rs7903146 polymorphism and type 2 diabetes mellitus: a meta-analysis of 115,809 subjects

Diabetology & Metabolic Syndrome201911:56

https://doi.org/10.1186/s13098-019-0451-9

  • Received: 5 May 2019
  • Accepted: 24 June 2019
  • Published:

Abstract

Background

Some genetic association studies tried to investigate potential associations of Transcription Factor 7 Like 2 (TCF7L2) rs7903146 polymorphism with type 2 diabetes mellitus (T2DM). However, the results of these studies were not consistent. Thus, we performed the present meta-analysis to explore associations between TCF7L2 rs7903146 polymorphism and T2DM in a larger pooled population.

Methods

Systematic literature research of PubMed, Web of Science and Embase was performed to identify eligible studies for pooled analyses. I2 statistics were employed to assess between-study heterogeneities. If I2 was greater than 50%, random-effect models (REMs) would be used to pool the data. Otherwise, fixed-effect models (FEMs) would be applied for synthetic analyses.

Results

Totally 68 studies with 115,809 subjects were included for analyses. The pooled analyses showed that TCF7L2 rs7903146 (dominant model: p < 0.0001; recessive model: p < 0.0001; over-dominant model: p < 0.0001; allele model: p < 0.0001) polymorphism was significantly associated with susceptibility to T2DM in overall population. Further subgroup analyses revealed similar significant findings in both Asians and Caucasians.

Conclusions

In conclusion, our findings supported that TCF7L2 rs7903146 polymorphism could be used to identify individuals at high risk of developing T2DM in Asians and Caucasians.

Keywords

  • Transcription Factor 7 Like 2 (TCF7L2)
  • rs7903146 polymorphism
  • Type 2 diabetes mellitus (T2DM)
  • Meta-analysis

Background

Type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia caused by insufficient responses to insulin, is the most prevalent type of metabolic disorder, and it is estimated that over 344 million people are currently affected by this disease worldwide [1, 2]. So far, the exact pathogenesis of T2DM is still not fully understood. However, past genome-wide association studies already identified over 100 genetic loci that were significantly associated with an increased susceptibility to T2DM, which supported that inherit factors were crucial for its occurrence and development [3, 4].

Transcription Factor 7 Like 2 (TCF7L2) gene encodes T cell transcription factor 4, a transcription factor of the Wnt/β-catenin signaling pathway that is vital for embryogenesis of the pancreas islet and regulation of blood glucose [5, 6]. Recently, some genome-wide association studies found that TCF7L2 rs7903146 polymorphism could significantly affect individual susceptibility to T2DM in certain populations [7, 8]. Since then, many genetic association studies were performed in diverse populations to estimate potential associations between TCF7L2 rs7903146 polymorphism and T2DM, with inconsistent results. In 2018, Ding et al. [9] already performed a meta-analysis to assess association between TCF7L2 rs7903146 polymorphism and T2DM, but only 28 studies were included by the authors and many eligible studies were missed. Therefore, we conducted an updated meta-analysis of all relevant studies published before May 2019 to more comprehensively analyze the effects of TCF7L2 rs7903146 polymorphism on individual susceptibility to T2DM in a larger pooled population.

Methods

The current meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [10].

Literature search and inclusion criteria

Potentially relevant articles were searched in PubMed, Medline and Web of Science using the following key words: “TCF7L2”, “Transcription Factor 7 Like 2”, “polymorphism”, “variant”, “mutation”, “SNP”, “genotype”, “allele”, “type 2 diabetes”, “type II diabetes” and “T2DM”. The initial literature search was performed in January 2019 and the latest update was finished in May 2019. Moreover, we also screened the references of all retrieved articles to identify other potential relevant studies.

Included studies must meet all the following criteria: (1) genetic association studies on associations between TCF7L2 rs7903146 polymorphism and T2DM in human beings; (2) provide genotypic/allelic frequency of TCF7L2 rs7903146 polymorphism in cases and controls; (3) full text in English available. For duplicate reports, only the most complete one was included. Studies were excluded if one of the following criteria was fulfilled: (1) not about TCF7L2 rs7903146 polymorphism and T2DM; (2) studies that were not performed in human beings; (3) case reports or case series; (4) reviews, comments and conference presentations.

Data extraction and quality assessment

The following data were extracted from included studies: (1) Last name of first author; (2) Year of publication; (3) Country where the study was conducted and ethnicity of study participants; (4) type of disease; (5) the number of cases and controls; and (6) genotypic/allelic distributions of TCF7L2 rs7903146 polymorphism in cases and controls. The probability value (p value) of Hardy–Weinberg equilibrium (HWE) was also calculated. When necessary, we wrote to the corresponding authors for extra information. We used the Newcastle–Ottawa scale (NOS) to assess the quality of eligible studies [11]. This scale has a score range of zero to nine, and studies with a score of more than seven were thought to be of high quality. Data extraction and quality assessment were performed by two independent reviewers. Any disagreement between two reviewers was solved by discussion until a consensus was reached.

Statistical analyses

We used Review Manager Version 5.3.3 (The Cochrane Collaboration, Software Update) to conduct statistical analyses. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate strength of associations between TCF7L2 rs7903146 polymorphism and T2DM in dominant, recessive, over-dominant and allele models. Statistical significances of pooled analyses were determined by the Z test, with a p value of 0.05 or less was defined as statistically significant. I2 statistics were employed to assess between-study heterogeneities. If I2 was greater than 50%, random-effect models (REMs) would be used to pool the data on account of significant heterogeneities. Otherwise, fixed-effect models (FEMs) would be used for synthetic analyses. Subgroup analyses by ethnicity of participants were subsequently performed to evaluate effects of ethnic background on investigated genetic associations. Sensitivity analyses were carried out to test the stability of pooled results by omitting one study each time and re-perform analyses based on the results of the remaining studies. Publication biases were evaluated with funnel plots.

Results

Characteristics of included studies

The initial literature search found 946 potential relevant articles. After exclusion of irrelevant and duplicate articles by reading titles and abstracts, 278 potentially relevant articles were retrieved for eligibility assessment. Another 210 articles were subsequently excluded after reading the full text. Finally, a total of 68 studies that met the inclusion criteria of our meta-analysis were included (Fig. 1). Baseline characteristics of included studies were shown in Table 1.
Fig. 1
Fig. 1

Flowchart of study selection for the present study

Table 1

The characteristics of included studies

First author, year

Country

Ethnicity

Type of disease

Sample size

Genotypes (wtwt/wtmt/mtmt)

p value for HWE

NOS score

Cases

Controls

rs7903146 C/T

 Acharya 2015

Saudi Arabia

South Asian

T2DM

359/351

131/137/91

132/143/76

0.002

8

 Al-Sinani 2015

Oman

South Asian

T2DM

992/294

NA

NA

NA

7

 Anjum 2018

China

East Asian

T2DM

339/191

160/117/62

110/56/25

< 0.001

7

 Assmann 2014

Brazil

Mixed

T2DM

953/535

382/415/156

261/215/59

0.147

8

 Barra 2012

Brazil

Mixed

T2DM

113/139

49/47/17

70/63/6

0.076

7

 Barros 2014

Brazil

Mixed

T2DM

108/109

53/49/6

58/40/11

0.304

7

 Beloso 2018

Uruguay

Mixed

T2DM

177/133

84/66/27

71/47/15

0.104

7

 Bielicki 2019

Poland

Caucasian

T2DM

121/479

69/45/7

285/172/22

0.539

7

 Bodhini 2007

India

South Asian

T2DM

1031/1038

462/455/114

555/391/92

0.055

8

 Cai 2019

China

East Asian

T2DM

296/446

197/83/16

287/147/12

0.180

8

 Cauchi 2006

France

Caucasian

T2DM

2367/2499

787/1149/431

1208/1060/231

0.944

8

 Chandak 2007

India

South Asian

T2DM

955/399

391/423/141

205/160/34

0.726

8

 Chang 2007

Taiwan

East Asian

T2DM

760/760

NA

NA

NA

7

 Chidambaram 2016

India

South Asian

T2DM

877/838

NA

NA

NA

7

 Corella 2016

Spain

Caucasian

T2DM

3411/3607

1158/1680/573

1612/1569/426

0.140

8

 Dahlgren 2017

Sweden

Caucasian

T2DM

168/885

67/83/18

496/327/62

0.421

8

 Danquah 2013

Germany

Caucasian

T2DM

674/375

273/323/78

182/165/28

0.257

7

 De Silva 2007

UK

Caucasian

T2DM

601/2099

211/299/91

1032/887/180

0.586

7

 El-Lebedy 2016

Egypt

Caucasian

T2DM

180/210

48/126/6

112/95/3

< 0.001

8

 Erkoç Kaya 2017

Turkey

Caucasian

T2DM

171/120

58/95/18

57/47/16

0.215

7

 Ezzidi 2009

Tunisia

Caucasian

T2DM

863/511

250/396/217

181/235/95

0.227

8

 Groves 2006

UK

Caucasian

T2DM

2001/2476

771/960/270

1175/1084/217

0.139

8

 Guewo-Fokeng 2015

Cameroon

African

T2DM

74/74

37/30/7

37/37/0

0.004

7

 Gupta 2010

India

South Asian

T2DM

195/161

55/96/44

62/78/21

0.647

8

 Hayashi 2007

Japan

East Asian

T2DM

1619/1069

1450/165/4

980/85/2

0.146

8

 Horikoshi 2007

Japan

East Asian

T2DM

1174/823

1051/119/4

770/51/2

0.243

8

 Hsiao 2017

Taiwan

East Asian

T2DM

562/986

497/62/3

933/52/1

0.755

7

 Humphries 2016

UK

Caucasian

T2DM

1459/2493

601/665/193

1295/1001/197

0.854

7

 Humphries 2016

UK

South Asian

T2DM

837/300

366/375/96

163/111/26

0.260

7

 Humphries 2016

UK

African

T2DM

307/311

141/136/30

161/124/26

0.759

7

 Hussain 2014

India

South Asian

T2DM

123/82

45/63/15

43/35/4

0.350

7

 Isakova 2019

Kyrgyzstan

Caucasian

T2DM

114/109

91/20/3

89/16/4

0.009

8

 Jia 2016

China

East Asian

T2DM

248/267

125/73/50

165/74/28

< 0.001

8

 Kalantari 2019

Iran

South Asian

T2DM

530/420

155/241/134

187/173/60

0.056

7

 Katsoulis 2018

Greece

Caucasian

T2DM

148/80

30/104/14

54/23/3

0.779

7

 Khan 2015

India

South Asian

T2DM

42/98

13/18/11

57/33/8

0.312

7

 Khan 2015

India

South Asian

T2DM

250/250

92/120/38

144/87/19

0.255

7

 Kimber 2007

UK

Caucasian

T2DM

3225/3291

1405/1459/361

1714/1329/248

0.663

8

 Kong 2015

China

East Asian

T2DM

5169/4560

NA

NA

NA

7

 Kunika 2008

Japan

East Asian

T2DM

1422/1423

1246/171/5

1309/111/3

0.689

8

 Löfvenborg 2019

Sweden

Caucasian

T2DM

1242/1530

NA

NA

NA

7

 Marquezine 2008

Brazil

Mixed

T2DM

285/1681

83/160/42

684/833/164

< 0.001

8

 Mayans 2007

Sweden

Caucasian

T2DM

824/820

452/318/54

532/253/35

0.481

8

 Miranda-Lora 2017

Mexico

Mixed

T2DM

156/212

115/38/3

157/51/4

0.952

8

 Miyake 2008

Japan

East Asian

T2DM

2154/1834

1921/228/5

1696/137/1

0.295

8

 Moran 2015

Venezuela

African

T2DM

70/73

26/35/9

46/22/5

0.307

8

 Musavi 2015

Iran

South Asian

T2DM

70/100

19/36/15

45/48/7

0.222

7

 Ouhaibi-Djellouli 2014

Algeria

African

T2DM

76/644

16/41/19

228/287/129

0.027

8

 Palizban 2017

Iran

South Asian

T2DM

204/80

60/95/49

32/41/7

0.224

8

 Palmer 2011

USA

Mixed

T2DM

982/1039

NA

NA

NA

7

 Papandreou 2019

Spain

Caucasian

T2DM

869/244

382/383/104

106/103/35

0.225

8

 Plengvidhya 2018

Thailand

East Asian

T2DM

500/500

429/67/4

456/44/0

0.303

8

 Pourahmadi 2015

Iran

South Asian

T2DM

200/200

109/68/23

126/59/15

0.037

8

 Rees 2008

UK

South Asian

T2DM

828/432

352/360/116

222/166/44

0.122

8

 Reyes-López 2019

Mexico

Mixed

T2DM

23/83

14/6/3

59/24/0

0.124

7

 Saadi 2008

United Arab Emirates

South Asian

T2DM

180/188

56/103/21

71/94/23

0.339

7

 Scott 2006

USA

Mixed

T2DM

1151/953

NA

NA

NA

7

 Tabara 2009

Japan

East Asian

T2DM

481/398

434/45/2

372/26/0

0.501

8

 Turki 2013

Tunisia

South Asian

T2DM

895/878

255/432/208

330/414/134

0.824

7

 Uma Jyothi 2015

India

South Asian

T2DM

758/621

341/326/83

391/193/37

0.048

7

 van Vliet-Ostaptchouk 2007

Netherlands

Caucasian

T2DM

496/907

203/221/72

459/365/83

0.397

7

 Včelák 2012

Czech Republic

Caucasian

T2DM

347/376

148/156/43

205/147/24

0.731

8

 Wang 2013

China

East Asian

T2DM

1842/7777

1553/283/6

6718/1032/27

0.057

8

 Wrzosek 2019

Poland

Caucasian

T2DM

129/345

67/50/12

219/113/13

0.738

8

 Yako 2015

South Africa

African

T2DM

152/328

66/74/12

184/129/15

0.199

8

 Yu 2009

USA

Mixed

T2DM

686/305

355/271/60

170/111/24

0.330

8

 Zhang 2016

China

East Asian

T2DM

227/5284

200/24/3

4567/701/16

0.045

8

 Zheng 2012

China

East Asian

T2DM

227/152

202/24/1

139/13/0

0.582

8

 Zhu 2017

China

East Asian

T2DM

497/782

478/19/0

740/41/1

0.584

8

 Zhuang 2018

China

East Asian

T2DM

90/96

54/26/10

69/24/3

0.611

7

T2DM type 2 diabetes mellitus, wt Wild type, mt mutant type, HWE Hardy–Weinberg equilibrium, NOS Newcastle–ottawa scale, NA not available

TCF7L2 rs7903146 polymorphism and T2DM

The results of overall and subgroup analyses were summarized in Table 2. Totally 68 studies with 115,809 subjects were included for analyses, the pooled analyses showed that TCF7L2 rs7903146 (dominant model: p < 0.0001, OR = 0.66, 95% CI 0.63–0.70; recessive model: p < 0.0001, OR = 1.64, 95% CI 1.56–1.73; over-dominant model: p < 0.0001, OR = 1.27, 95% CI 1.21–1.34; allele model: p < 0.0001, OR = 0.71, 95% CI 0.68–0.74) polymorphism was significantly associated with susceptibility to T2DM in overall population. Further subgroup analyses revealed similar significant findings in both Asians and Caucasians (Table 2).
Table 2

Results of overall and subgroup analyses

Variables

Sample size

Dominant comparison

Recessive comparison

Over-dominant comparison

Allele comparison

p value OR (95% CI)

p value OR (95% CI)

p value OR (95% CI)

p value OR (95% CI)

Overall

51,656/64,153

<0.0001 0.66 (0.63–0.70)

<0.0001 1.64 (1.56–1.73)

<0.0001 1.27 (1.21–1.34)

<0.0001 0.71 (0.68–0.74)

Caucasian

19,410/23,456

<0.0001 0.64 (0.58–0.70)

<0.0001 1.64 (1.54–1.75)

<0.0001 1.31 (1.21–1.43)

<0.0001 0.70 (0.65–0.75)

East Asian

17,607/27,348

<0.0001 0.73 (0.63–0.83)

<0.0001 1.90 (1.46–2.46)

0.0006 1.28 (1.11–1.48)

<0.0001 0.74 (0.66–0.83)

South Asian

9326/6730

<0.0001 0.63 (0.59–0.68)

<0.0001 1.65 (1.48–1.84)

<0.0001 1.24 (1.16–1.33)

<0.0001 0.65 (0.60–0.71)

OR odds ratio, CI confidence interval, NA not available, T2DM type 2 diabetes mellitus

Sensitivity analyses

We performed sensitivity analyses by deleting one individual study each time to test the effects of individual study on pooled results. No any altered results were observed in overall and subgroup comparisons, which indicated that our findings were statistically robust.

Publication biases

We used funnel plots to assess publication biases. We did not find obvious asymmetry of funnel plots in any comparisons, which suggested that our findings were unlikely to be impacted by severe publication biases (Additional file 1: Fig. S1).

Discussion

Despite prominent advancements achieved in drug therapy over the last few decades, T2DM and its associated vascular complications are still leading causes of death and disability around the world [12, 13]. The exact cause of T2DM is still largely unclear in spite of extensive explorations. However, the obvious familial aggregation tendency of T2DM indicated that genetic factors played significant parts in its pathogenesis [14]. Thus, identify genetic biomarkers is of particularly importance for an early diagnosis and a better prognosis of T2DM patients.

TCF7L2, a box-containing transcription factor that is vital for blood glucose homeostasis, is considered to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway [15], and pre-clinical studies also found that TCF7L2 expression is positively associated with insulin gene expression in human islets [16]. Considering the vital role of TCF7L2 in regulating blood glucose, many genetic association studies were performed in diverse populations to investigate whether functional TCF7L2 polymorphisms could impact individual susceptibility to T2DM. To our knowledge, this is to date the most comprehensive meta-analysis on association between TCF7L2 rs7903146 polymorphism and T2DM, and our pooled analyses suggested that TCF7L2 rs7903146 polymorphism was significantly associated with T2DM in both Asians and Caucasians. The stabilities of synthetic results were evaluated by sensitivity analyses, and no alterations of results were observed in any comparisons, which suggested that our findings were statistically robust. Significant heterogeneities were detected for dominant and allele comparisons, thus pooled analyses for these two genetic models were performed with REMs. But in further subgroup analyses, an obvious reduction tendency of heterogeneity was found in both Asians and Caucasians, which suggested that differences in ethnic background could largely explain observed heterogeneities between studies. Nevertheless, it is worth noting that the obvious heterogeneities existed among included studies indicated that the distribution of TCF7L2 rs7903146 polymorphism varies greatly from population to population. Therefore, the genetic association between TCF7L2 rs7903146 polymorphism and T2DM may be ethnic-specific, and we should not generalize the subgroup analyses results to a broader population.

There are several points that need to be pointed out about the current study. First, the exact underlying molecular mechanisms of our positive findings remains to be explored, but we speculated that TCF7L2 rs7903146 polymorphism may lead to alternations in gene expression or changes in protein structure, which may subsequently affect biological functions of TCF7L2, impact insulin secretion or decrease sensitivity to insulin, and ultimately affect individual susceptibility to T2DM. Second, the pathogenic mechanism of T2DM is extremely complex, and hence despite our positive findings, it is unlikely that a single gene polymorphism could significantly contribute to its development, and thus we strongly recommend further studies to perform haplotype analyses and explore potential gene–gene interactions [17, 18]. Third, to more precisely measure the effects of certain genetic factors on disease occurrence and development, gene-environmental interactions should also be considered. However, since included studies only focused on the effects of TCF7L2 rs7903146 polymorphism on individual susceptibility to T2DM, such analyses were not applicable in the current meta-analysis. But to better elucidate the underlying pathogenesis mechanisms of T2DM, future studies should try to investigate the interaction of TCF7L2 gene polymorphisms with potential pathogenic environmental factors such as unhealthy diets or lack of exercise [19]. Our meta-analysis certainly has some limitations. Firstly, although methodology qualities of included studies were generally good, it should be noted that we did not have access to genotypic distributions of investigated polymorphisms according to base characteristics of study subjects. Therefore, our results were derived from unadjusted estimations, and failure to conduct further adjusted analyses for baseline characteristics of participants such as age, gender and co-morbidity conditions may influence the veracity of our findings [20, 21]. Secondly, significant heterogeneities were detected in certain subgroup comparisons, which indicated that the inconsistent results of included studies could not be fully explained by differences in ethnic background, and other unmeasured characteristics of participants may also partially attribute to between-study heterogeneities [22]. Thirdly, since only published articles were eligible for analyses, although funnel plots revealed no obvious publication biases, we still could not rule out the possibility of potential publication biases [23]. Taken these limitations into consideration, the results of the current study should be interpreted with caution.

Conclusions

In conclusion, our findings indicated that TCF7L2 rs7903146 polymorphism was significantly associated with altered susceptibility to T2DM in both Asians and Caucasians. These results supported that this polymorphism may be used to identify individuals at high risk of developing T2DM in Asians and Caucasians. Further well-designed studies need to explore possible associations between other TCF7L2 gene polymorphisms and T2DM.

Abbreviations

TCF7L2

Transcription Factor 7 Like 2

T2DM: 

type 2 diabetes mellitus

HWE: 

Hardy–Weinberg equilibrium

NOS: 

Newcastle–Ottawa scale

REM: 

random-effect model

FEM: 

fixed-effect model

Declarations

Acknowledgements

None.

Funding

None.

Authors’ contributions

LL conceived of the study, participated in its design. LL and JW conducted the systematic literature review. JW performed data analyses. LL drafted the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Endocrinology, Shengzhou People’s Hospital, No. 666 Dangui Road of Sanjiang Street, Shaoxing, 312400, Zhejiang, China

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