Abstract
Transcription factor 7-like 2 has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups in recent years. In the Chinese Han population in particular, numerous studies have evaluated the association between the rs11196218A/G polymorphism of the transcription factor 7-like 2 gene and type 2 diabetes mellitus. However, the results have been inconsistent, so we performed a meta-analysis to assess the association. Odds ratio and 95% confidence interval values were calculated using a random-effects model or a fixed-effects model based on heterogeneity analysis. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Subgroup analyses were conducted based on conformity with Hardy-Weinberg equilibrium in the control group as well as on other variables, such as age, sex and body mass index. Sensitivity analysis was also performed to detect heterogeneity and to assess the stability of the results. In total, 10 case-control studies comprising 7,491 cases and 12,968 controls were included in this meta-analysis. The combined analysis indicated that the rs11196218A/G polymorphism was not associated with type 2 diabetes mellitus (G vs. A, OR=1.04, 95% CI=0.97–1.13, p=0.28). The subgroup analyses also did not show any association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus. Furthermore, the results of the subgroup analyses indicated that the absence of an association was not influenced by age, sex or body mass index. The results of the sensitivity analysis verified the reliability and stability of this meta-analysis. In conclusion, this study indicated that there is no significant association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus in the Chinese Han population.
Type 2 diabetes mellitus (T2DM); Transcription factor 7-like 2 (TCF7L2); rs11196218A/G polymorphism; Meta-analysis
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a complex metabolic disease resulting from a
combination of environmental and genetic factors (11. Hansen L, Pedersen O. Genetics of type 2 diabetes mellitus:
status and perspective. Diabetes Obes Metab. 2005;7(1):122–35,
10.1111/dom.2005.7.issue-2.
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). With the development of society and the improvement of people's
standard of living, the prevalence of T2DM is increasing rapidly all around the
world. T2DM is very harmful to human health and life, and it also confers a heavy
burden on society.
The transcription factor 7-like 2 (TCF7L2) gene, located on chromosome 10q25 (22. Duval A, Busson-Leconiat M, Berger R, Hamelin R. Assignment of
the TCF-4 (TCF7L2) to human chromosome band 10q25.3. Cytogenet Cell Genet.
2000;88(3-4):264–5, 10.1159/000015534.
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), is part of the Wnt signaling pathway (33. Yi FH, Brubaker PL, Jin TR. TCF-4 mediates cell type-specific
regulation gene expression by β-catenin and glycogen synthase kinase-3β. J Biol
Chem. 2005;280(2):1457–64, 10.1074/jbc.M411487200.
http://dx.doi.org/10.1074/jbc.M411487200...
) and has been shown to be strongly associated
with an increased risk of T2DM in Icelandic (44. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R,
Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2)
gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–3,
10.1038/ng1732.
http://dx.doi.org/10.1038/ng1732...
), European (55. Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, et al.
(2006) Transcription factor TCF7L2 genetic study in the French population:
expression in human β-cells and adipose tissue and strong association with type
2 diabetes. Diabetes.2006;55(10): 2903-8.–1111. Potapov VA, Shamkhalova MN, Smetanina SA, Bel'chikova LN,
Suplotova LA, Shestakova MV, et al. Polymorphic markers TCF7L2 rs12255372 and
SLC30A8 rs13266634 confer susceptibility to type 2 diabetes in a Russian
population. Genetika. 2010;46(8):1123–31.), West African (1212. Lehman DM, Hunt KJ, Leach RJ, Hamlington J, Arya R, Abboud HE,
et al. Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its
upstream region are associated with type 2 diabetes and age of onset in Mexican
Americans. Diabetes. 2007;56(2):389–93, 10.2337/db06-0860.
http://dx.doi.org/10.2337/db06-0860...
), southern Asian (1313. Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna
P, Hattersley AT, et al. Common variants in the TCF7L2 gene are strongly
associated with type 2 diabetes mellitus in the Indian population. Diabetologia.
2007;50(1):63–7, 10.1007/s00125-006-0502-2.
http://dx.doi.org/10.1007/s00125-006-050...
), eastern Asian (1414. Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S. Replication
study for the association of TCF7L2 with susceptibility to type 2 diabetes in a
Japanese population. Diabetologia. 2007;50(5):980–4,
10.1007/s00125-007-0618-z.
http://dx.doi.org/10.1007/s00125-007-061...
), and Chinese
(1515. Zhu H. Common Variants of the TCF7L2 Gene with Type 2 Diabetes
and Impaired Glucose Regulation in a Chinese Han Population. Master thesis.
2011. [Article in Chinese].–1919. Zhai YJ, Zhao JZ, You HF, Pang C, Yin L, Guo T, et al.
Association of the rs11196218 polymorphism in TCF7L2 with type
2 diabetes mellitus in Asian population. Meta Gene.2014;2:332–41,
10.1016/j.mgene.2014.04.006.
http://dx.doi.org/10.1016/j.mgene.2014.0...
) populations. The TCF7L2 gene is regarded as one of the most
important genes for determining genetic susceptibility to T2DM that has been
identified in humans so far.
With the growth of research efforts, studies on the association between this variation and T2DM have been extensively performed in China, but the results are disputable. Overall, the most significant risk locus identified in Chinese individuals is rs11196218. Therefore, only the rs11196218A/G polymorphism was considered in the present meta-analysis.
In contrast to a single study, meta-analyses are based on all available studies,
which has improved the statistical power for exploring the above associations and
has led to more reliable conclusions in recent years (2020. Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J. A method
for meta-analysis of molecular association studies. Stat Med.
2005;24(9):1291–306, 10.1002/(ISSN)1097-0258.
http://dx.doi.org/10.1002/(ISSN)1097-025...
). Therefore, in the present study, a meta-analysis was
performed to allow a valuable conclusion to be drawn regarding the relationship
between the rs11196218A/G polymorphism and T2DM risk in the Chinese Han
population.
MATERIALS AND METHODS
Our study adhered to the PRISMA Statement regarding the reporting of systematic
reviews and meta-analyses (2121. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA statement. Int J
Surg. 2010;8(5):336–41, 10.1016/j.ijsu.2010.02.007.
http://dx.doi.org/10.1016/j.ijsu.2010.02...
).
Search strategy
In this meta-analysis, we searched articles in PubMed, Elsevier, SpringerLink, Embase, the Cochrane Library, ISI Web of Science, Google Scholar and the China National Knowledge Infrastructure (CNKI). The search languages included English and Chinese. The following key words and subject terms were used: TCF7L2, transcription factor 7-like 2, rs11196218, diabetes mellitus, type 2, type 2 diabetes mellitus, T2DM, and T2D. The reference lists of eligible studies and relevant review papers were additionally identified via a manual search on this topic. The last research update was performed on July 15, 2014.
Inclusion and exclusion criteria
The primary studies included in our meta-analysis had to meet the following criteria: (1) the association between the TCF7L2 polymorphism (rs11196218) and T2DM risk in the Chinese Han population was clearly evaluated, (2) the diagnosis of T2DM and the sources of the cases and controls were clearly described, (3) a case-control study design was employed, and (4) original data and sufficient information were provided to estimate the odds ratio (OR) and the corresponding 95% confidence interval (95% CI). The major reasons for exclusion were as follows: (1) duplicate data were presented; (2) the article consisted of an abstract, comment, or review or focused on pathological mechanisms; and (3) more than one article was published by the same author using the same data series, in which case the most recent published paper or the paper with the largest sample size was selected.
Quality assessment
The Newcastle-Ottawa Scale (NOS) (2222. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et
al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised
studies in meta-analyses.2011.
http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 20 Aug
2012.
http://www.ohri.ca/programs/clinical_epi...
) was
used to assess the quality of the studies included in our meta-analysis. The NOS
contains eight items and is categorized into three dimensions: selection,
comparability and exposure, for case-control studies. In particular, the
selection dimension contains four items, the comparability dimension contains
one item, and the exposure dimension contains three items. A star system is used
to allow semi-quantitative assessment of study quality, and a study can be
awarded a maximum of one star for each numbered item within the selection and
exposure categories. Meanwhile, a maximum of two stars can be given for
comparability. The NOS ranges from zero up to nine stars, as follows:
high-quality study: more than seven stars; medium-quality study: between four
and six stars; poor-quality study: less than four stars.
Data extraction
For quality control, the data were extracted by two reviewers using a standardized extraction form. If the information on the genotype distribution was inadequate, we tried to contact the authors by telephone or e-mail. The following information was extracted from each article: the last name of the first author, the year of publication, the region, the numbers of cases and controls, the source of the controls, the numbers of genotypes for cases and controls, matching factors, and the Hardy-Weinberg equilibrium (HWE) in each control group. Disagreement was resolved by consulting a third reviewer.
Ethics statement
This article reports a meta-analysis of data obtained from previous studies. All of the data were anonymized before analysis. We also confirmed that none of the data involved competing interests.
Statistical analysis
In this meta-analysis, OR and 95% CIvalues were
used to assess the association between a polymorphism of the TCF7L2 gene
(rs11196218: G vs. A) and T2DM risk. In addition, statistical significance was
assessed using a Z-test, and p<0.05
indicated statistical significance for the association. The model selection was
based on the heterogeneity test; therefore, the
χ2-based Q-test was performed in
this study (2323. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in
systematic reviews. Ann Intern Med. 1997;127(9):820–6,
10.7326/0003-4819-127-9-199711010-00008.
http://dx.doi.org/10.7326/0003-4819-127-...
). When the
Q-test yielded a p-value of more than
0.10, a fixed-effects model was used (2424. Mantel N, Haenszel W. Statistical aspects of the analysis of
data from retrospective studies of disease. J Natl Cancer Inst.
1959;22(4):719–48.); otherwise, a random-effects model was applied (2525. DerSimonian R, Laird N. Meta-analysis in clinical trials.
Control Clin Trials. 1986;7(3):177–88,
10.1016/0197-2456(86)90046-2.
http://dx.doi.org/10.1016/0197-2456(86)9...
). Heterogeneity was also assessed using
the I2 test. The
I2statistic was specifically documented for the
percentage of study variability observed due to heterogeneity rather than chance
(I2=0–25%, no heterogeneity;
I2=25–50%, moderate heterogeneity;
I2=50–75%, high heterogeneity;
I2=75–100%, extreme heterogeneity) (2626. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60,
10.1136/bmj.327.7414.557.
http://dx.doi.org/10.1136/bmj.327.7414.5...
).
Subgroup analyses were performed based on HWE. Specifically, the
p-values for HWE in the control group were determined using
the Pearson chi-square test, regardless of whether the authors provided these
values. HWE is the principal law of population genetic studies: if
p>0.05, the focus conforms to HWE, and the control
samples are representative. In Europeans, when excessive calories are consumed,
variation in TCF7L2 can cause impaired β-cell function, indicating that body
mass index (BMI) can influence the effect size of TCF7L2 variants; hence, these
two factors will ultimately affect each other (2727. Haupt A, Thamer C, Heni M, Ketterer C, Machann J, Schick F, et
al. Gene variants of TCF7L2 influence weight loss and body composition during
lifestyle intervention in a population at risk for type 2 diabetes. Diabetes.
2010;59(3):747–50, 10.2337/db09-1050.
http://dx.doi.org/10.2337/db09-1050...
–2929. Xavier GS, Loder MK, McDonald A, Tarasov AI, Carzaniga R, et al.
TCF7L2 regulates late events in insulin secretion from pancreatic islet β-Cells.
Diabetes. 2009;58(4):894–5, 10.2337/db08-1187.
http://dx.doi.org/10.2337/db08-1187...
). This interaction may
also exist in Asians. For this reason, we considered whether age, sex and BMI
were matched between cases and controls in our subgroup analyses. For example,
the studies showing a significant difference in age (p<0.05)
between the cases and the controls were assigned to the incomparability subgroup
of age, whereas those exhibiting p>0.05 were assigned to the
comparability subgroup. However, due to the limited data in the studies,
subgroup analyses based on environment were not conducted.
Sensitivity analysis was also performed to search for heterogeneity and to assess the stability of the results. One case-control study was omitted each time to reflect the influence of each dataset on the pooled OR.
Additionally, funnel plots were used to evaluate publication bias. All p-values were two tailed. Review Manager 5.0 (2011, The Cochrane Collaboration) software was used to perform the meta-analysis.
RESULTS
Studies and data included in this meta-analysis
In total, 295 articles were relevant to our search terms, of which 285 papers
were excluded. Thus, 10 case-control studies (1515. Zhu H. Common Variants of the TCF7L2 Gene with Type 2 Diabetes
and Impaired Glucose Regulation in a Chinese Han Population. Master thesis.
2011. [Article in Chinese].–1919. Zhai YJ, Zhao JZ, You HF, Pang C, Yin L, Guo T, et al.
Association of the rs11196218 polymorphism in TCF7L2 with type
2 diabetes mellitus in Asian population. Meta Gene.2014;2:332–41,
10.1016/j.mgene.2014.04.006.
http://dx.doi.org/10.1016/j.mgene.2014.0...
,) comprising 7,491
cases of T2DM and 12,968 controls were ultimately included in this meta-analysis
(Figure 1). All of these studies were
published from 2007–2014.
The characteristics of these studies are summarized in Table 1. The genotype frequency of the single nucleotide
polymorphism (SNP) was consistent with HWE in the control group
(p>0.05) in all studies except for two (3232. Luo YY, Wang HY, Han XY, Ren Q, Wang F, Zhang XY, et al.
Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in
East Asian population. Diabetes Research and Clinical Practice. 2009; 85:
139-46, 10.1016/j.diabres.2009.04.024.
http://dx.doi.org/10.1016/j.diabres.2009...
,3333. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du YP, et al.
Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and
TCF7L2 as susceptibility genes in a Han Chinese Cohort. PLoS ONE.
2010;5(2):e9153, 10.1371/journal.pone.0009153.
http://dx.doi.org/10.1371/journal.pone.0...
). The quality assessment of all included studies, evaluated
according to the NOS, is provided in Table
2. Most studies were of high quality in terms of selection and
exposure. However, the quality of comparability was relativity low, as only 3
studies (1515. Zhu H. Common Variants of the TCF7L2 Gene with Type 2 Diabetes
and Impaired Glucose Regulation in a Chinese Han Population. Master thesis.
2011. [Article in Chinese].,3333. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du YP, et al.
Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and
TCF7L2 as susceptibility genes in a Han Chinese Cohort. PLoS ONE.
2010;5(2):e9153, 10.1371/journal.pone.0009153.
http://dx.doi.org/10.1371/journal.pone.0...
,3434. Qiao H, Zhang XL, Zhao XD, Zhao YL, Xu LD, Sun HM, et al.
Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern
Chinese population. Gene. 2012;495(2):115–9,
10.1016/j.gene.2011.12.055.
http://dx.doi.org/10.1016/j.gene.2011.12...
) were
comparable with the controls regarding age, sex and BMI.
Association between rs11196218A/G polymorphism and T2DM risk
Using the heterogeneity test, we detected heterogeneity among the studies in comparisons of the risk of carrying allele G. Thus, a random-effects model was applied for the meta-analysis. The results indicated that the rs11196218A/G polymorphism was not associated with the risk of T2DM (G vs. A: OR=1.04, 95% CI=0.97–1.13, p=0.28; heterogeneity test χ2=17.71, p=0.04, I2=49%; Figure 2).
Meta-analysis of the association between the rs11196218A/G polymorphism and T2DM risk (G vs. A). n indicates the total number of G alleles, and N indicates the total number of G alleles plus A alleles.
The subgroup meta-analysis of the studies that exhibited consistency with HWE in the control group also showed that there was no association between the rs11196218A/G polymorphism and T2DM risk (G vs. A: OR=1.08, 95% CI=0.98-1.19, p=0.12; heterogeneity test χ2=15.79, p=0.03, I2=56%; Figure 3).
Meta-analysis of the association between the rs11196218A/G polymorphism and T2DM risk (subgroup analyses for HWE in the control group: G vs. A). n indicates the total number of G alleles, and N indicates the total number of G alleles plus A alleles.
The subgroup meta-analysis of the studies based on age indicated that there was no significant association between the rs11196218A/G polymorphism and T2DM risk (subgroup of age comparability: OR=1.11, 95% CI=0.96-1.28, p=0.18; heterogeneity test χ2=14.81, p=0.01, I2=66%; subgroup of age incomparability: OR=1.00, 95% CI=0.94-1.06, p=0.93; heterogeneity test χ2=1.45, p=0.69, I2=0%).
The subgroup meta-analysis of the studies based on sex demonstrated that there was no significant association between the rs11196218A/G polymorphism and T2DM risk (subgroup of sex comparability: OR=1.10, 95% CI=0.98-1.24, p=0.12; heterogeneity test χ2=13.04, p=0.02, I2=62%; subgroup of sex incomparability: OR=0.98, 95% CI=0.91-1.05, p=0.49; heterogeneity test χ2=1.58, p=0.66, I2=0%).
Finally, the subgroup meta-analysis of the studies based on BMI illustrated that there was no significant association between the polymorphism and T2DM risk (subgroup of BMI comparability: OR=1.03, 95% CI=0.90-1.17, p=0.72; heterogeneity test χ2=6.21, p=0.10, I2=52%; subgroup of BMI incomparability: OR=1.06, 95% CI=0.96-1.18, p=0.26; heterogeneity test χ2=11.32, p=0.05, I2=56%).
Sensitivity analysis
A single study included in the meta-analysis was omitted each time to reflect the influence of each dataset on the pooled OR values. We found that no single study could change the pooled results (Table 3), which indicated that the results were relatively reliable.
Publication bias
The shape of the funnel plots was symmetrical, suggesting that there was no evidence of publication bias for the rs11196218A/G polymorphism (Figure 4).
Funnel plot analysis to detect publication bias (G vs. A of the rs11196218A/G polymorphism). Each point represents an independent study on the indicated association. The dark point represents two overlapping articles.
DISCUSSION
Since the initial discovery that TCF7L2 is strongly associated with an increased risk
of T2DM in Icelandic populations in 2006 (44. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R,
Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2)
gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–3,
10.1038/ng1732.
http://dx.doi.org/10.1038/ng1732...
),
many replication studies have confirmed the role of TCF7L2 in conferring
susceptibility to T2DM in different populations and ethnic groups (55. Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, et al.
(2006) Transcription factor TCF7L2 genetic study in the French population:
expression in human β-cells and adipose tissue and strong association with type
2 diabetes. Diabetes.2006;55(10): 2903-8.,77. Lyssenko V, Lupi R, Marchetti P, Guerra SD, Orho-Melander M,
Almgren P, et al. Mechanisms by which common variants in the TCF7L2 gene
increase risk of type 2 diabetes. J Clini Invest. 2007;117(8):2155–63,
10.1172/JCI30706.
http://dx.doi.org/10.1172/JCI30706...
,1111. Potapov VA, Shamkhalova MN, Smetanina SA, Bel'chikova LN,
Suplotova LA, Shestakova MV, et al. Polymorphic markers TCF7L2 rs12255372 and
SLC30A8 rs13266634 confer susceptibility to type 2 diabetes in a Russian
population. Genetika. 2010;46(8):1123–31.,1414. Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S. Replication
study for the association of TCF7L2 with susceptibility to type 2 diabetes in a
Japanese population. Diabetologia. 2007;50(5):980–4,
10.1007/s00125-007-0618-z.
http://dx.doi.org/10.1007/s00125-007-061...
,3838. Miyake K, Horikawa Y, Hara K, Yasuda K, Osawa H, Furuta H, et
al. Association of TCF7L2 polymorphisms with susceptibility to type 2 diabetes
in 4,087 Japanese subjects. J Hum Genet. 2008;53(2):174–80,
10.1007/s10038-007-0231-5.
http://dx.doi.org/10.1007/s10038-007-023...
,3939. Palizban A, Nikpour M, Salehi R, Maracy MR. Association of a
common variant in TCF7L2 gene with type 2 diabetes mellitus in a Persian
population. Clin Exp Med. 2012;12(2):115–9,
10.1007/s10238-011-0144-7.
http://dx.doi.org/10.1007/s10238-011-014...
), especially for the rs7903146C/T
polymorphism. However, in the Chinese population, rs7903146 is very rare, and
several studies have indicated that rs11196218 is the most significant risk variant
(1717. Ng MC, Tam CH, Lam VK, So WY, Ma RC. Replication and
identification of novel variants at TCF7L2 associated with type 2 diabetes in
Hong Kong Chinese. J Clin Endocr Metab. 2007;92(9):3733–7,
10.1210/jc.2007-0849.
http://dx.doi.org/10.1210/jc.2007-0849...
). Nevertheless, the results regarding
the rs11196218A/G polymorphism and T2DM risk have been inconsistent for the Chinese
Han population. Certain studies (1515. Zhu H. Common Variants of the TCF7L2 Gene with Type 2 Diabetes
and Impaired Glucose Regulation in a Chinese Han Population. Master thesis.
2011. [Article in Chinese].–1919. Zhai YJ, Zhao JZ, You HF, Pang C, Yin L, Guo T, et al.
Association of the rs11196218 polymorphism in TCF7L2 with type
2 diabetes mellitus in Asian population. Meta Gene.2014;2:332–41,
10.1016/j.mgene.2014.04.006.
http://dx.doi.org/10.1016/j.mgene.2014.0...
) confirmed that the G allele of the
rs11196218A/G polymorphism was significantly associated with T2DM risk, whereas
studies by Ma (3030. Ma C. Relationships of rs13266634 and rs11196218 polymorphisms
in SLC30A8 (solute carrier family 30, member 8) and TCF7L2 (transcription factor
7-like 2 genes with type 2 diabetes in Southern Chinese Han Population) Master
thesis. 2010. [Article in Chinese].), Zheng et al. (3131. Zheng XY, Ren W, Zhang SH, Liu JJ, Li SF, Li JC, et al.
Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and
PCSK2) and proinsulin conversion in a Chinese population. Mol Biol Rep. 2012;
39(1): 17-23, 10.1007/s11033-011-0705-6.
http://dx.doi.org/10.1007/s11033-011-070...
), Luo et al. (3232. Luo YY, Wang HY, Han XY, Ren Q, Wang F, Zhang XY, et al.
Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in
East Asian population. Diabetes Research and Clinical Practice. 2009; 85:
139-46, 10.1016/j.diabres.2009.04.024.
http://dx.doi.org/10.1016/j.diabres.2009...
), Wen et al. (3333. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du YP, et al.
Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and
TCF7L2 as susceptibility genes in a Han Chinese Cohort. PLoS ONE.
2010;5(2):e9153, 10.1371/journal.pone.0009153.
http://dx.doi.org/10.1371/journal.pone.0...
) and
Qiao et al. (3434. Qiao H, Zhang XL, Zhao XD, Zhao YL, Xu LD, Sun HM, et al.
Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern
Chinese population. Gene. 2012;495(2):115–9,
10.1016/j.gene.2011.12.055.
http://dx.doi.org/10.1016/j.gene.2011.12...
) did not find a significant
association between the rs11196218A/G polymorphism and T2DM risk in the Chinese Han
population. Therefore, to resolve the conflict among these studies, we performed a
meta-analysis to assess the association between the rs11196218A/G polymorphism and
T2DM risk.
Previously, Luo et al. (3232. Luo YY, Wang HY, Han XY, Ren Q, Wang F, Zhang XY, et al.
Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in
East Asian population. Diabetes Research and Clinical Practice. 2009; 85:
139-46, 10.1016/j.diabres.2009.04.024.
http://dx.doi.org/10.1016/j.diabres.2009...
) conducted a
meta-analysis to evaluate the effect of TCF7L2 on genetic susceptibility to T2DM in
the East Asian population. However, only one article analyzed included samples from
the Chinese Han population. In the current study, to increase the statistical power
of the analysis, a larger amount of data was collected from the literature to
perform an up-to-date meta-analysis for the Chinese Han population.
Our meta-analysis, which included 7,491 T2DM cases and 12,968 controls from 10
case-control studies, explored the association between rs11196218A/G and T2DM risk.
Overall, we did not find that the rs11196218A/G polymorphism was significantly
associated with an increased risk of T2DM in the Chinese Han population, which is
consistent with the findings of Ma (3030. Ma C. Relationships of rs13266634 and rs11196218 polymorphisms
in SLC30A8 (solute carrier family 30, member 8) and TCF7L2 (transcription factor
7-like 2 genes with type 2 diabetes in Southern Chinese Han Population) Master
thesis. 2010. [Article in Chinese].),
Zheng et al. (3131. Zheng XY, Ren W, Zhang SH, Liu JJ, Li SF, Li JC, et al.
Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and
PCSK2) and proinsulin conversion in a Chinese population. Mol Biol Rep. 2012;
39(1): 17-23, 10.1007/s11033-011-0705-6.
http://dx.doi.org/10.1007/s11033-011-070...
), Luo et al. (3232. Luo YY, Wang HY, Han XY, Ren Q, Wang F, Zhang XY, et al.
Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in
East Asian population. Diabetes Research and Clinical Practice. 2009; 85:
139-46, 10.1016/j.diabres.2009.04.024.
http://dx.doi.org/10.1016/j.diabres.2009...
), Wen et al.(3333. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du YP, et al.
Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and
TCF7L2 as susceptibility genes in a Han Chinese Cohort. PLoS ONE.
2010;5(2):e9153, 10.1371/journal.pone.0009153.
http://dx.doi.org/10.1371/journal.pone.0...
) and Qiao et al. (3434. Qiao H, Zhang XL, Zhao XD, Zhao YL, Xu LD, Sun HM, et al.
Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern
Chinese population. Gene. 2012;495(2):115–9,
10.1016/j.gene.2011.12.055.
http://dx.doi.org/10.1016/j.gene.2011.12...
).
However, a previous meta-analysis performed by Luo et al. (3232. Luo YY, Wang HY, Han XY, Ren Q, Wang F, Zhang XY, et al.
Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in
East Asian population. Diabetes Research and Clinical Practice. 2009; 85:
139-46, 10.1016/j.diabres.2009.04.024.
http://dx.doi.org/10.1016/j.diabres.2009...
) found that rs11196218 showed a marginal association with
T2DM risk (OR=1.09, 95% CI=1.00-1.19,
p=0.059). The most plausible explanation for this discrepancy
is the different genetic backgrounds associated with different ethnic groups, areas
and population substructures.
In the present study, obvious heterogeneity was observed in the comparisons among
studies. Thus, a random-effects model was applied for the meta-analysis, after which
we conducted a sensitivity analysis to identify the source of the heterogeneity.
After omitting the study by Ng et al. (1717. Ng MC, Tam CH, Lam VK, So WY, Ma RC. Replication and
identification of novel variants at TCF7L2 associated with type 2 diabetes in
Hong Kong Chinese. J Clin Endocr Metab. 2007;92(9):3733–7,
10.1210/jc.2007-0849.
http://dx.doi.org/10.1210/jc.2007-0849...
)
from the analysis, there was no heterogeneity among the remaining studies. One
plausible explanation for the influential role of this study was that the
populations examined by Ng et al. (1717. Ng MC, Tam CH, Lam VK, So WY, Ma RC. Replication and
identification of novel variants at TCF7L2 associated with type 2 diabetes in
Hong Kong Chinese. J Clin Endocr Metab. 2007;92(9):3733–7,
10.1210/jc.2007-0849.
http://dx.doi.org/10.1210/jc.2007-0849...
)
resided in the metropolis of Hong Kong; as the residents of Hong Kong emigrated from
different areas of China, they have probably undergone population admixture.
Moreover, T2DM is a complex hereditary disease, so the historical immigration,
complex ancestries, population movement, and recent intermarriages with other ethnic
groups that have occurred in Hong Kong may have resulted in different risk factors
in different people (4040. Xu SH, Yin XY, Li SL, Jin WF, Lou HY, Yang L, et al. Genomic
dissection of population substructure of Han Chinese and its implication in
association studies. Am J Hum Genet. 2009;85(6):762–74,
10.1016/j.ajhg.2009.10.015.
http://dx.doi.org/10.1016/j.ajhg.2009.10...
). Therefore, the
genetic origins of risk may be relatively different between this region and other
areas. Pritchard et al. (4141. Pritchard JK, Donnelly P. Case-Control Studies of Association in
Structured or Admixed Populations. Theor. Popul. Biol.
2001;60(3):227–37.) also suggested
that low diversity may be sufficient to lead to different results. However, although
heterogeneity was observed among studies, the results of the sensitivity analysis
verified the reliability and stability of the present meta-analysis.
T2DM is a complex hereditary disease caused by genetic and environmental factors (1). Other confounding factors, such as age, sex, BMI, the environment and sophisticated gene-gene and gene-environment interactions, may also affect the results of studies on T2DM. Thus, the subgroup analyses in the present study were also conducted based on variables such as age, sex and BMI. However, the results indicated that the association of the rs11196218A/G polymorphism with T2DM was not influenced by age, sex or BMI in the studied population. Due to the limited data available in the studies analyzed, subgroup analyses based on the environment and gene-gene and gene-environment interactions were not conducted.
There were certain advantages of our meta-analysis. First, to the best of our knowledge, this is the most comprehensive meta-analysis of the association between the rs11196218A/G polymorphism of the TCF7L2 gene and T2DM risk in the Chinese Han population conducted to date, and our analysis had improved statistical power for exploring this association. Second, the protocol for this meta-analysis, using explicit methods and criteria for study selection, data extraction, and data analysis, was well designed before it was initiated. Third, a stringent searching strategy based on computer-assisted and manual searches was applied to include as many eligible studies as possible. Finally, the quality of the studies included in our meta-analysis was satisfactory; in fact, each article exhibited at least five stars. However, there were still certain limitations of this meta-analysis. First, the sample sizes of several of the studies included in our meta-analysis were relatively small. Second, due to the limited information on environment and lifestyle available the included studies, it was not possible to perform a subgroup meta-analysis or an interaction analysis based on environment or lifestyle. Finally, similar to a case-control study, a meta-analysis is a retrospective study, and recall bias might also exist.
In conclusion, we did not find any association between the TCF7L2 gene rs11196218A/G polymorphism and T2DM risk in the Chinese Han population. To achieve a better and more comprehensive understanding of the association between TCF7L2 gene polymorphisms and T2DM risk, we suggest that studies including large samples and different ethnicities and lifestyles and examining sophisticated gene-gene and gene-environment interactions should also be considered in future analyses.
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Publication Dates
-
Publication in this collection
Aug 2015
History
-
Received
29 Jan 2015 -
Reviewed
20 Mar 2015 -
Accepted
12 May 2015