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. 2019 Jul 5;11:56. doi: 10.1186/s13098-019-0451-9

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

Liying Lou 1,✉, Jingjing Wang 1, Jing Wang 1
PMCID: PMC6612193  PMID: 31312259

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.

Electronic supplementary material

The online version of this article (10.1186/s13098-019-0451-9) contains supplementary material, which is available to authorized users.

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

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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
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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)
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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.

Additional file

13098_2019_451_MOESM1_ESM.docx (92.5KB, docx)

Additional file 1: Figure S1. Funnel plots.

Acknowledgements

None.

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

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.

Funding

None.

Availability of data and materials

The current study was based on results of relevant published studies.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Liying Lou, Email: liyinglou69@163.com.

Jingjing Wang, Email: wangjjwl@yeah.net.

Jing Wang, Email: w123angjing@126.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

13098_2019_451_MOESM1_ESM.docx (92.5KB, docx)

Additional file 1: Figure S1. Funnel plots.

Data Availability Statement

The current study was based on results of relevant published studies.

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