Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects

doi:10.1016/j.diabres.2008.01.008

Diabetes Research and Clinical Practice

Volume 80, Issue 3, June 2008, Pages 392-398

https://doi.org/10.1016/j.diabres.2008.01.008 Get rights and content

Abstract

Aims

The prevalence of type 2 diabetes mellitus (DM) among Emirati subjects is one of the highest in the world. This has been attributed to rising prevalence of obesity acting on genetically susceptible individuals. We analyzed the associations between TCF7L2 polymorphism and DM, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects.

Methods

We genotyped the two TCF7L2 single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146 in 368 adult subjects. Homeostatic model assessment (HOMA) was used to assess beta cell function (HOMA2-%B) and insulin resistance (HOMA2-IR). The SNP genotypes were analyzed against disease stage [normal glucose = 0 (n = 188), pre-diabetes = 1 (n = 85), and DM = 2 (n = 95)] and against clinical and biochemical measures. Age and sex were included as covariates in all association analyses. Additional adjustments were made for body mass index (BMI) and waist circumference in several analyses.

Results

Diabetes disease stage was marginally significantly associated with the frequency of the T variant at rs12255372 (p = 0.057; adjusted p = 0.017) but not at rs7903146 (p = 0.5; adjusted p = 0.2). Comparison between subjects with normal glucose and the combined DM/pre-diabetes showed a significant association with rs12255372 (OR 1.47, CI 1.04–2.08; p = 0.03) but not with rs7903146 (OR 1.16, CI 0.81–1.64; p = 0.4). We found no association with metabolic syndrome, or with insulin and glucose levels, HOMA2-%B or HOMA2-IR. The age-standardized prevalence rate for metabolic syndrome was 43.9% in men and 42.1% in women.

Conclusion

These data suggest that TCF7L2 variants are associated with increased risk for DM in Emirati subjects. We also demonstrate a high prevalence of the metabolic syndrome in this population.

Introduction

The prevalence of type 2 diabetes mellitus (DM) in the United Arab Emirates (UAE) and other Gulf countries is one of the highest in the world [1], [2], [3], [4], [5]. In addition to a sedentary lifestyle related to recent affluence leading to obesity and insulin resistance [1], [2], [5], [6], the rising prevalence has been attributed to genetic predisposition, although most of the genes involved have not yet been determined. The strongest known association between DM and genetic markers is that with the recently mapped single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) [7]. A recent genome-wide study confirmed the above reported association and identified significant associations for four other susceptibility loci [8]. Candidate-gene studies have also reported many DM-associated loci such as the coding variants in the nuclear receptor PPARG (P12A) and the potassium channel KCNJ11 (E23K) [9], [10]. While some of the loci have strong support from several populations, no locus shows evidence for association in all studied populations. For example, the six TCF7L2 variants initially reported to be associated with DM in the Icelandic study [7], and replicated in various ethnic groups [11], [12], [13], [14], [15], [16], [17], [18], [19], were less common in Pima Indians as compared to samples of European origin and none was associated with DM [20]. Similarly, several studies have demonstrated that Pro12Ala polymorphism of the PPARG gene is associated with decreased risk of diabetes in many European and Asian populations [9], [21], [22] but this association was not found in Qatari and Tunisian subjects [23], [24].

To our knowledge, the genetic influence of TCF7L2 has not been studied in Emirati or other Gulf Arab subjects. The objective of our study was to analyze the associations between TCF7L2 polymorphism and the risk of DM in a representative sample of Emirati subjects living in Al Ain, UAE. We also investigated whether TCF7L2 genotypes were associated with the metabolic syndrome and markers of beta cell function and insulin resistance. We genotyped the SNPs rs7903146 and rs12255372 since they showed the strongest association with risk of DM in the study by Grant et al. [7].

Section snippets

Participants

Subjects participated in a cross-sectional, population-based study of the prevalence of diabetes and its complications in Al Ain, UAE as described in detail elsewhere [2]. The study was designed to enroll 100 subjects with DM in order to be able to estimate the prevalence of any complication that occurs in 50% of subjects with DM with a standard error of 0.05. With a prevalence rate of DM in the adult population of 25% [1], we targeted a total sample size of 400 subjects. A random sample of 600

Results

We genotyped the two TCF7L2 SNPs (rs7903146 and rs12255372) in a population-based sample of 368 Emirati subjects (188 subjects with normal glucose values, 85 with pre-diabetes and 95 with recently diagnosed or with known DM). Five subjects were excluded due to the unavailability of their genomic DNA. Anthropometric and clinical characteristics as well as results of the biochemical measurements are shown in Table 1. The prevalence of the metabolic syndrome was 19.3% among subjects with normal

Discussion

The frequency of the minor T allele for rs7903146 (37.2%) and rs12255372 (33.8%) in our subjects with normal glucose was slightly higher than that previously reported in European populations [7] and much higher than that seen in Asian populations [18], [19], [31]. The frequency of the minor T allele for rs7903146 however was quite similar to that of Moroccans [17]. We found a statistically significant association for rs12255372 but not rs7903146 with risk of DM. Although the strongest

Conclusion

Our results suggest that TCF7L2 variants are associated with increased risk for DM in Emirati subjects. We found no association with metabolic syndrome, insulin resistance or beta cell function. We also demonstrate a high prevalence of metabolic syndrome in this population. While the clinical applications of the association between TCF7L2 variants and DM remain to be fully determined [35], [41], it is important to note that lifestyle intervention has been shown to efficiently reduce the risk

Conflict of interest

The authors state that they have no conflict of interest.

Acknowledgments

This study was supported by a research grant from UAE University and UAE Red Crescent. We thank all members of the “National Survey of the Prevalence of Diabetes and its Complications in Al-Ain” committee for their support. We are also grateful for Mrs. Hala Shehouri for data collection, Mrs. Shaikha Al Marar and Mr. Awad Al Essa for data entry, and Ms. Lina Sejaan and Mr. Javed Yasin for their technical assistance. We also thank Dr. Bassam Ali for reviewing the manuscript.

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Population-based Genome-wide association studies showed variants in KCNJ11 and TCF7L2 genes are associated with type 2 diabetes mellitus (T2DM). Our study was aimed to identify the association of common variants of these genes with T2DM and related traits in West Bengal, India.
Six single nucleotide polymorphisms (SNPs) of two genes (KCNJ11- rs5219, rs5215, rs5213, and TCF7L2-rs7903146, rs12255372, rs10885409) were genotyped in 200 T2DM patients and 200 ethnically matched normal individuals.
Results showed the association of four SNPs (rs5219, rs5213, rs7903146, and rs12255372) with T2DMwhere odd ratios (OR) were 1.46, 1.44, 1.48, and 1.42 respectively. Iindividuals carrying 4 risk alleles (T of rs7903146, T of rs12255372, A of rs5219, and G of rs5213) have 3 fold risk (p = 0.007, OR = 2.81; 95%CI: 1.32–5.98) of T2DM. We observed a significant association between individuals carrying 4 risk alleles and glycemic risk factors (fasting blood glucose, p-0.008 & postprandial blood glucose, p-0.007) as well as a cardiovascular risk factor (VLDL levels, p-0.036).
Our study identified four common variants of KCNJ11 and TCF7L2 genes which areassociated with T2DM in the population of West Bengal, India.
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Transcription factor 7-like 2 (TCF7L2) plays an important role in insulin resistance and peroxisome proliferator-activated receptor γ (PPARG) is directly targeted by antidiabetic drug. This study was designed to investigate the association of genetic variants in TCF7L2 and PPARG and T2DM susceptibility. Blood samples were collected from 472 subjects (221 controls and 251 T2DM cases) after ethical approval. All subjects were genotyped for two single nucleotide polymorphisms (SNPs) in each gene TCF7L2 (+9017G>T and -41435C>T) and PPARG (-44458C>G, -17676A>G) using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) and amplification-refractory mutation system (ARMS-PCR). The TCF7L241435C>T polymorphism showed significantly higher frequency of 'TT' genotype in controls (12.2%) (P = 0.023). Haplotype 'GC*' of TCF7L2 (+9017G>T,-41435C>T) showed significant association with T2DM (P = 0.043). We conclude that individuals with 'GTG*' allelic combination were at significantly higher risk for T2DM (OR = 5.1, P=0.0002 respectively) whereas GCG* and GTA* allelic combinations showed significant protection against T2DM.The individual SNPs in TCF7L2 and PPARG genes were non-informative in genotyping analysis but showed significant risk for T2DM when analyzed together.
Transcription factor 7-like 2 gene, rs12255372 (G/T) variant and susceptibility to type 2 diabetes mellitus in North Indians
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Citation Excerpt :
The present case-control study established the association of 1.91 folds increased diabetes risk with TT homozygous in comparison to homozygous GG genotype. This result is inconsistent with the previously reported studies in different populations (Wang et al., 2007; Saadi et al., 2008; Alami et al., 2012). Bodhini et al. observed a significant association between the T allele of rs12255372 (G/T) SNP and T2DM in South Indians (Bodhini et al., 2007).
Genetic polymorphisms of the Transcription Factor 7-Like 2 (TCF7L2) gene have been shown to be strongly associated with susceptibility to type 2 diabetes mellitus (T2DM) and its related complications across several ethnicities.
The aim of the present study was to investigate the association of rs12255372 (G/T) polymorphism in TCF7L2 gene with the risk of T2DM in the Indian population.
We included a total of 712 human subjects (327 T2DM subjects and 385 healthy controls) for various anthropometric, biochemical and genetic parameters. Genotyping of TCF7L2 gene was carried out using the PCR-RFLP method.
Significantly higher values of body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), and body fat (%) were observed in T2DM subjects than controls (p ≤.001). Dyslipidemia represented by higher levels of triglycerides and reduced values of high-density lipoprotein (HDL) was more predominant in T2DM subjects compared to healthy controls. Both microvascular and macrovascular complications were predominant in T2DM patients than controls. The risk genotype (TT) frequency of TCF7L2 gene was significantly higher in T2DM subjects compared to controls (19.4% vs. 9.8%). The “T” allele was more predominant in T2DM subjects than healthy controls. Logistic regression analysis of the data indicates that the TT genotype of TCF7L2 gene is associated with appox. 2-fold increased risk of developing T2DM (OR = 1.91 95% CI (1.16–3.16); p = .014). Interestingly, no significant association among the genotypic distribution of metabolic traits in T2DM and healthy subjects.
The present study established a significant association of TCF7L2 gene (rs12255372 (G/T) polymorphism) with a higher risk of T2DM in the North Indian population.
Diabetes as a risk factor for Alzheimer's disease in the Middle East and its shared pathological mediators
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The incidence of Alzheimer’s disease (AD) has risen exponentially worldwide over the past decade. A growing body of research indicates that AD is linked to diabetes mellitus (DM) and suggests that impaired insulin signaling acts as a crucial risk factor in determining the progression of this devastating disease. Many studies suggest people with diabetes, especially type 2 diabetes, are at higher risk of eventually developing Alzheimer's dementia or other dementias. Despite nationwide efforts to increase awareness, the prevalence of Diabetes Mellitus (DM) has risen significantly in the Middle East and North African (MENA) region which might be due to rapid urbanization, lifestyle changes, lack of physical activity and rise in obesity. Growing body of evidence indicates that DM and AD are linked because both conditions involve impaired glucose homeostasis and altered brain function. Current theories and hypothesis clearly implicate that defective insulin signaling in the brain contributes to synaptic dysfunction and cognitive deficits in AD. In the periphery, low-grade chronic inflammation leads to insulin resistance followed by tissue deterioration. Thus insulin resistance acts as a bridge between DM and AD. There is pressing need to understand on how DM increases the risk of AD as well as the underlying mechanisms, due to the projected increase in age related disorders. Here we aim to review the incidence of AD and DM in the Middle East and the possible link between insulin signaling and ApoE carrier status on Aβ aggregation, tau hyperphosphorylation, inflammation, oxidative stress and mitochondrial dysfunction in AD. We also critically reviewed mutation studies in Arab population which might influence DM induced AD. In addition, recent clinical trials and animal studies conducted to evaluate the efficiency of anti-diabetic drugs have been reviewed.
Investigating the association of rs7903146 of TCF7L2 gene, rs5219 of KCNJ11 gene, rs10946398 of CDKAL1 gene, and rs9939609 of FTO gene with type 2 diabetes mellitus in Emirati population
2019, Meta Gene
Citation Excerpt :
Some populations were more prone to this chronic disease compared to the others; suggesting the effect of the genetic background on its susceptibility (Haghvirdizadeh et al., 2015). Contrary to the previous study on an Emirati population (Saadi et al., 2008), we observed association of rs7903146 with T2DM. In the previous study in Emirati population, the number of T2DM patients was 90 in comparison to 264 in this study.
Type 2 diabetes mellitus is a metabolic condition associated with increased risk of multiple organ complications. Genetic variations in TCF7L2, KCNJ11, CDKAL1, and FTO are shown to be linked to T2DM in many ethnic groups. T.
To investigate the possible associations of these single nucleotide polymorphisms with the susceptibility of T2DM among Emirati population.
The study included 264 unrelated diabetic patients and 153 unrelated healthy controls from Emirati population. DNA was extracted from participants' saliva samples and genotyped for four SNPs rs7903146, rs5219, rs10946398, and rs9939609 using TaqMan® real-Time PCR assays. The associations between the SNPs and T2DM were tested using a multiple logistic regression model incorporating age, gender, body mass index, and hypertension as covariates.
A significant association was observed between the genotype distribution of the SNP rs7903146 (TCF7L2) and T2DM (p = .0063, OR = 1.80). Further analyses indicated that SNP rs7903146 was possibly interacting with age and BMI to influence the susceptibility to T2DM. In addition, rs5219 (KCNJ11) showed significant link with two anthropometric parameters; BMI (p = .033) and diastolic blood pressure (p = .041), rs10946398 (CDKAL1) affected glycosylated hemoglobin (p = .025) and fasting blood glucose (p = .036), and rs9939609 (FTO) affected BMI (p = .014), systolic blood pressure (p = .044), and fasting blood glucose (p = .034).
These findings demonstrate that rs7903146 (TCF7L2) is a risk for T2DM susceptibility among the United Arab Emirates population, while rs5219, rs10946398 and rs9939609 variants may not directly related to T2DM development but to some of its risk factors and related traits.
Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism
2019, Molecular Metabolism
Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism.
We generated Tcf7l2^F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis.
Here we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue.
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Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects

Abstract

Aims

Methods

Results

Conclusion

Introduction

Section snippets

Participants

Results

Discussion

Conclusion

Conflict of interest

Acknowledgments

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Diabetes Metab.

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Prevalence of diabetes mellitus and its complications in a population-based sample in Al Ain, United Arab Emirates

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