Elsevier

Pathologie Biologie

Volume 58, Issue 6, December 2010, Pages 426-429
Pathologie Biologie

Original article
TCF7L2 is associated with type 2 diabetes in nonobese individuals from TunisiaTCF7L2 est associé au diabète de type 2 chez les non-obèses de Tunisie

https://doi.org/10.1016/j.patbio.2009.01.003Get rights and content

Abstract

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was associated with type 2 diabetes (T2D) in most populations worldwide. In individuals of European descent, the association with T2D was recently found to be modulated by obesity status. However, further studies are necessary to clarify if whether interaction exists among subjects of non-European descent. In the present study, we analyzed the association of rs7903146 with T2D in 90 nonobese (Body Mass Index [BMI] < 25 kg/m2), 171 overweight (25  BMI < 30 kg/m2) et 98 obese (BMI  30 kg/m2) individuals from Tunisia. The T allele was nominally associated with T2D in nonobese subjects (Odds Ratio [OR] = 3.24 [1.10–9.53], P = 0.021) whereas no effect was detected in overweight (P = 0.3) and obese (P = 0.22) individuals. Consequently, the same risk allele decreased susceptibility to obesity in T2D subjects (OR = 0.47 [0.23–0.94], P = 0.029) but not in normoglycemic controls (P = 0.44). When analyzed all together, no allelic association was observed with T2D (P = 0.20) whereas an artefactual association with decreased obesity (0.59 [0.38–0.90], P = 0.013) was detected. As in Europeans, TCF7L2 is therefore not a risk factor for obesity in Tunisians, but its effect on T2D risk is modulated by obesity. In conclusion, the TCF7L2 rs7903146 T allele is nominally associated with T2D susceptibility in nonobese individuals from Tunisia.

Résumé

L’allèle T (rs7903146) du facteur de transcription TCF7L2 a été associé au diabète de type 2 (DT2) dans la plupart des populations à travers le monde. Chez des individus d’origine européenne, il a été montré que le niveau d’obésité modulait son association avec le DT2. Cependant, d’autres études sont nécessaires pour clarifier si cette interaction est aussi retrouvée chez des sujets non européens. Dans cette étude, nous avons analysé l’association du variant rs7903146 avec le DT2 chez 90 non-obèses (indice de masse corporel < 25 kg/m2), 171 individus en surpoids (25  IMC < 30 kg/m2) and 98 obèses (IMC  30 kg/m2) de Tunisie. L’allèle T était modestement associé avec le DT2 chez les individus non obèses (Odds Ratio [OR] = 3,24 [1,10–9,53], p = 0,021) alors qu’aucun effet n’a été détecté, ni chez les individus en surpoids (p = 0,3) ni chez les obèses (p = 0,22). Par conséquent, le même allèle à risque était aussi associé avec une baisse de susceptibilité à l’obésité chez les sujets DT2 (OR = 0,47 [0,23–0,94], p = 0,029) mais pas chez les individus normoglycémiques (p = 0,44). Quand on analyse tout le monde ensemble, aucune association allélique n’est observée avec le DT2 (p = 0,20) alors qu’une association artefactuelle est retrouvée avec une baisse du risque d’obésité (0,59 [0,38–0,90], p = 0,013). Tout comme chez les Européens, TCF7L2 n’est donc pas un facteur de risque d’obésité cependant son effet sur le risque de DT2 est modulé par l’obésité. En conclusion, l’allèle T du variant génétique rs7903146 de TCF7L2 est modestement associé au risque de DT2 chez les individus non obèses de Tunisie.

Introduction

Type 2 diabetes (T2D) involves a complex interaction between genetic and environmental factors with obesity established as a primary risk factor [1]. Variations within intron 3 of the transcription factor 7-like 2 (TCF7L2) gene were initially associated with increased risk for T2D in populations of European descent [2]. Then, Helgason et al. reported that the rs7903146 T allele may be the etiological ancestral allele [3]. This Single Nucleotide Polymorphism (SNP) has therefore been the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. The rs7903146 T allele has then been consistently associated with T2D in most ethnicities [4] and has been the SNP the most associated with T2D in Genome Wide Association Studies (GWAS) of Caucasian populations [5], [6], [7], [8], [9]. However, in populations of European descent, the rs7903146 T allele was also associated with lower Body Mass Index (BMI) in T2D individuals and with a higher risk for T2D in nonobese subjects [3], [10], [11], [12]. In developing countries that have been adopting a western lifestyle involving decreased physical activity and overconsumption of cheap, energy-dense food, the rates of obesity have tripled [13]. In Tunisia, according to the National Nutrition Survey 1996/97, the prevalence of obesity reaches 22,7% in women and 6,4% in men. We previously showed that TCF7L2 is strongly associated with T2D in Moroccans [4] but we needed to see if one could confirm such association in another population from the Maghreb and clarify if similar interactions with BMI exists in non-Europeans. In the present study, we first analyzed the association of the rs7903146 T allele with T2D in 90 nonobese (BMI < 25 kg/m2), 171 overweight (25  BMI < 30 kg/m2) and 98 obese (BMI  30 kg/m2) individuals from Tunisia. Then, in the same individuals, the effects of TCF7L2 on obesity prevalence were assessed in control and T2D subjects.

Section snippets

Subjects

The study design included 359 subjects. Their phenotypic characteristics are summarized in Table 1. Participants originated from north of Tunisia were recruited in the Endocrinology service at Charles Nicolle's hospital in Tunis and among members working in the Tunisian society of electricity and gas at Tunis. All participants signed an informed consent and our protocol was approved by local ethic committees.

Measures

BMI is defined as the individual's body weight (kg) divided by the square of their

Discussion

In Europeans, it was recently suggested that genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in nonobese individuals [14]. An interaction between TCF7L2 and adiposity may be due to better β-cell compensation in obese individuals [15], [16].

In the present study, we found that TCF7L2 is nominally associated with T2D

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    However, in the same Arabs population in Tunisia, Ezzidi and coworkers [21] found a significant association of UCSNP19 with diabetes risk, while Ouederni and coworkers [20] found no association. Of the five SNPs of the TCF7L2 gene (rs7903146; rs4506565; rs12243326; rs12255372; DG10S478) investigated in eight studies[19,24–30] across four population groups (Ghanaian, Tunisian, Morocco and Nigerians); only one (rs7903146) was associated with type 2 diabetes. Amidst the two SNPs (rs1800630 and rs1800629) of the TNF-α gene were investigated in four studies [31–33], in two non-specified populations (Tunisian and Egyptian), rs1800630 was found to be related to type 2 diabetes in a Tunisian population [32].

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    The remaining three studies conducted in Saudi, Emirati and an additional Tunisian population showed a weak or no association with p-values of 0.675, 0.397 and 0.671 respectively (Alsmadi et al., 2008a; Bouhaha et al., 2009; Saadi et al., 2008). For TCF7L2 rs1225372, neither of the studies conducted among Saudis and Emiratis showed a significant association with T2D with a p-value of 0.601 and 0.08 respectively.TCF7L2 rs7903146 was found to be studied in six Arab studies, namely Tunisians (Alsmadi et al., 2008a; Bouhaha et al., 2009; Cauchi et al., 2007; Ereqat et al., 2009; Ezzidi et al., 2009a; Saadi et al., 2008), Moroccans(Cauchi et al., 2007), Palestinians (Ereqat et al., 2009), Saudis (Alsmadi et al., 2008a), and Emiratis (Saadi et al., 2008). Similarly, six studies that looked into the association of TCF7L2 rs7903146 with T2D were considered for the Caucasian population, namely Swedish (Mayans et al., 2007), Dutch (van Vliet-Ostaptchouk et al., 2007), Scottish (Kimber et al., 2007), British (De Silva et al., 2007), Norwegian (Thorsby et al., 2009), and French (Cauchi et al., 2006).

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